N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds

ABSTRACT

This invention pertains to novel substituted N/aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides useful as analgesics, and methods of administering analgesia, which comprises the systemic administration to mammals of such compounds, and pharmaceutical compositions containing such compounds, wherein the novel compounds have the general formula: ##STR1## including optically active isomeric forms, and the pharmaceutically acceptable acid addition salts thereof, wherein R, R 1 , R 2 , R 3  and R 4  are defined in the disclosure.

The present invention relates to substitutedN-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides, and pharmaceuticalcompositions and methods employing such compounds.

BACKGROUND OF THE INVENTION

A number of patents disclose certainN-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides having therapeuticactivity. For example, U.S. Pat. No. 3,998,834, issued to Janssen et al.and assigned to Janssen Pharmaceuticals N. V., discloses certainN-phenyl-N-[4-(1-heterocyclic)piperidinyl]amide compounds useful asanalgesics. U.S. Pat. No. 4,584,303, issued to Huang et al. and assignedto The BOC Group, Inc., also discloses certainN-phenyl-N-[4-(1-heterocyclic)piperidinyl]amide compounds useful asanalgesics.

SUMMARY OF THE INVENTION

This invention pertains to novel substitutedN-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides useful asanalgesics, and methods of administering analgesia, which comprises thesystemic administration to mammals of such compounds, and pharmaceuticalcompositions containing such compounds, wherein the novel compounds havethe general formula: ##STR2## including optically active isomeric forms,and the pharmaceutically acceptable acid addition salts thereof,wherein:

R is an aryl group selected from the group consisting of Phenyl andsubstituted Phenyl, wherein the substituent groups on the phenyl groupare selected from the group consisting of .[.halogen.]..Iadd.halo.Iaddend., lower-alkoxy, and combinations thereof;

R₁ is an alkyl group selected from the group consisting of lower-alkyl,lower-alkenyl, and lower-alkoxy lower-alkyl, having from 2 to 6 carbonatoms;

R₂ is a heterocyclic lower-alkyl ring system selected from the groupconsisting of pyrrolyl lower-alkyl, pyrazolyl lower-alkyl, imidazolyllower-alkyl, imidazolinyl lower-alkyl, imidazolyl lower-thioalkyl,triazolyl lower-alkyl, triazolyl lower-thioalkyl, tetrazolyllower-alkyl, tetrazolyl lower-thioalkyl, thienyl lower-oxyalkyl, thienyllower-hydroxyalkyl, thien-3-yl lower-alkyl, furanyl lower-hydroxyalkyl,thiazolyl lower-alkyl, oxazolyl lower-alkyl, thiadiazolyl lower-alkyl,oxadiazolyl lower-alkyl, piperidinyl lower-alkyl, pyrimidinyllower-alkyl, pyridazinyl lower-alkyl, triazinyl lower-alkyl, indolyllower-alkyl, isoindolyl lower-alkyl, benzimidazolyl lower-alkyl,benzopyrazolyl lower-alkyl, benzoxazolyl lower-alkyl, benzopyranyllower-alkyl, benzodioxanyl lower-alkyl, benzothiazinyl lower-alkyl,quinazolinyl lower-alkyl, purinyl lower-alkyl, phthalimidyl lower-alkyl,naphthalenecarboxamidyl lower-alkyl, and naphthalenesulfamidyllower-alkyl, wherein the heterocyclic ring system may be unsubstitutedor substituted;

R₃ is selected from the group consisting of hydrogen, lower-alkoxycarbonyl and lower-alkoxy methyl; and

R₄ is selected from the group consisting of hydrogen and methyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the pretest invention possess very desirable analgesicactivities. In particular, the inventive compounds have central nervoussystem depressant properties which include analgesia, hypnosis,sedation, muscle relaxation, increased pain threshold, and barbiturateand/or generally anesthetic potentiation. Many of the compound providehighly potent analgesia with immediate onset and a short duration ofaction. These properties are highly desirable in circumstances whereacute sever pain must be eliminated over a short period of time, such asin anesthesiology. The preferred compounds of the present invention havebeen found to provide reduced rigidity at high doses, superior motorcoordination recovery, or less respiratory depressive and/orcardiovascular depressive activity when compared to fentanyl(N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide).

The compounds of the present invention may be used together with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions and can be administered to mammals such as man in amountssufficient to provide analgesic effects.

As set out above, the analgesic compounds of the present invention havethe general formula: ##STR3## including optically active isomeric forms,and the pharmaceutically acceptable acid addition salts thereof, whereinR, R₁, R₂, R₃ and R₄ are defined as set forth below:

R in Formula I above is an aryl group selected from the group consistingof Phenyl and substituted phenyl, wherein said substituents are selectedfrom the group consisting of .[.halogen.]. .Iadd.halo.Iaddend.,lower-alkoxy, and combinations thereof. Preferred substituents arefluoro and methoxy. The preferred position for attachment of asubstituent to the phenyl ring is at the 2 (ortho) position. In apreferred embodiment, R is selected from the group consisting of phenyl,2-fluorophenyl and 2-methoxyphenyl.

R₁ in Formula I above is selected from the group consisting oflower-alkyl, lower-alkenyl, and lower-alkoxy lower-alkyl having from 2to 6 carbon atoms. In a preferred embodiment, R₁ is selected from thegroup consisting of ethyl, ethenyl, methoxymethyl and 1-methoxyethyl.

R₂ in Formula I above is a heterocyclic lower-alkyl ring system selectedfrom the group consisting of monocyclic heterocyclic lower-alkyl ringsystems having 5 to 6 ring member atoms and fused bicyclic and tricyclicheterocyclic lower-alkyl ring systems having 5 to 6 ring member atoms ineach ring of the polycyclic ring system. The heteroatom is a memberselected from the group consisting of nitrogen, sulfur and oxygen.

In a preferred embodiment, the heterocyclic lower-alkyl ring system isselected from the group consisting of pyrrolyl lower-alkyl, pyrazolyllower-alkyl, imidazolyl lower-alkyl, imidazolinyl lower-alkyl,imidazolyl lower-thioalkyl, triazolyl lower-alkyl, triazolyllower-thioalkyl, tetrazolyl lower-alkyl, tetrazolyl lower-thioalkyl,thienyl lower-oxyalkyl, thienyl lower-hydroxyalkyl, thien-3-yllower-alkyl, furanyl lower-hydroxyalkyl, thiazolyl lower-alkyl, oxazolyllower-alkyl, thiadiazolyl lower-alkyl, oxadiazolyl lower-alkyl,piperidinyl lower-alkyl, pyrimidinyl lower-alkyl, pyridazinyllower-alkyl, triazinyl lower-alkyl, indolyl lower-alkyl, isoindolyllower-alkyl, benzimidazolyl lower-alkyl, benzopyrazolyl lower-alkyl,benzoxazolyl lower-alkyl, benzopyranyl lower-alkyl, benzodioxanyllower-alkyl, benzothiazinyl lower-alkyl, quinazolinyl lower-alkyl,purinyl lower-alkyl, phthalimidyl lower-alkyl, naphthalenecarboxamidyllower-alkyl, and naphthalenesulfamidyl lower-alkyl.

In a more preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,imidazolin-1-yl lower-alkyl, triazol-1-yl lower-alkyl, triazol-3-yllower-thioalkyl, tetrazol-1-yl lower-alkyl, tetrazol-2-yl lower-alkyl,tetrazol-5-yl lower-thioalkyl, thien-2-yl lower-oxyalkyl, thien-2-yllower-hydroxyalkyl, thien-3-yl lower-alkyl, furan-2-yllower-hydroxyalkyl, thiazol-5-yl lower-alkyl, oxazol-3-yl lower-alkyl,thiadiazol-2-yl lower-alkyl, oxadiazol-3-yl lower-alkyl, piperidin-1-yllower-alkyl, pyrimidin-1-yl lower-alkyl, pyridazin-1-yl lower-alkyl,triazin-1-yl lower-alkyl, indol-1-yl lower-alkyl, isoindol-2-yllower-alkyl, benzimidazol-1-yl lower-alkyl, benzimidazol-2-yllower-alkyl, benzopyrazol-3-yl lower-alkyl, benzoxazol-3-yl lower-alkyl,benzopyran-4-yl lower-alkyl, benzopyran-7-Yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzodioxan-8-yl lower-alkyl,benzothiazin-4-yl lower-alkyl, quinazolin-3-yl lower-alkyl, purin-1-yllower-alkyl, purin-7-yl lower-alkyl, N-phthalimidyl lower-alkyl,N-naphthalenecarboxamidyl lower-alkyl, and N-naphthalenesulfamidyllower-alkyl.

In a most preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,imidazolin-1-yl lower-alkyl, triazol-1-yl lower-alkyl, triazol-3-yllower-thioalkyl, tetrazol-1-yl lower-alkyl, tetrazol-2-yl lower-alkyl,tetrazol-5-yl lower-thioalkyl, furan-2-l lower-hydroxyalkyl, oxazol-3-yllower-alkyl, thiadiazol-2-yl lower-alkyl, oxadiazol-3-yl lower-alkyl,piperidin-1-yl lower-alkyl, pyrimidin-1-yl lower-alkyl, pyridazin-1-yllower-alkyl, triazin-1-yl lower-alkyl, indol-1-yl lower-alkyl,isoindol-2-yl lower-alkyl, benzimidazol-1-yl lower-alkyl,benzimidazol-2-yl lower-alkyl, benzopyrazol-3-yl lower-alkyl,benzoxazol-3-yl lower-alkyl, benzopyran-4-yl lower-alkyl,benzopyran-7-yl lower-alkyl, benzodioxan-2-yl lower-alkyl,benzodioxan-8-yl lower-alkyl, benzothiazin-4-yl lower-alkyl,quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl, purin-7-yllower-alkyl, N-phthalimidyl lower-alkyl, N-naphthalenecarboxamidyllower-alkyl, and N-naphthalenesulfamidyl lower-alkyl.

The heterocyclic ring may be unsubstituted or substituted, wherein thesubstituent group is independently selected from consisting of.[.halogen, oxygen.]. .Iadd.halo, oxo.Iaddend., hydroxyl, nitro, amino,.[.carbonyl,.]. lower-alkoxy carbonyl, lower-alkyl, lower-cycloalkyl,lower-alkoxy, .[.lower-thioalkyl,.]. halogenated lower-alkyl, aryl,halogenated aryl, heterocycles, and combinations thereof. In a preferredembodiment, the substituent group is selected from the group consistingof fluoro, chloro, iodo, .[.oxygen.]. .Iadd.oxo.Iaddend., nitro, amino,.[.carbonyl,.]. ethoxy carbonyl, methyl, ethyl, isopropyl, spiroethane,methoxy, .[.thiomethyl,.]. trifluoromethyl, phenyl, morpholinyl andcombinations thereof.

The lower-alkyl group is selected from the group consisting of branched-or unbranched-hydrocarbon groups containing from 1 to 7 carbon atoms.The lower-alkyl group may be substituted or unsubstituted, withsubstituent members independently selected from the group consisting of.[.oxygen.]. .Iadd.oxo.Iaddend., hydroxyl, sulfur, and combinationsthereof. In a preferred embodiment, the lower-alkyl group is selectedfrom the group consisting of methyl, ethyl, 2-hydroxyethyl, .Iadd.and.Iaddend.2-oxoethyl.[., and 2-thioethyl.]..

R₃ in Formula I above is selected from the group consisting of hydrogen,lower-alkoxy carbonyl and lower-alkoxy methyl. In a preferredembodiment, the R₃ group is selected from the group consisting ofhydrogen, methoxy carbonyl and methoxymethyl.

R₄ in Formula I above is selected hydrogen and methyl.

In a preferred embodiment, the compounds of the present invention havethe general formula: ##STR4## including optically active isomeric forms,and the pharmaceutically acceptable acid addition salts thereof, whereinR and R₁ are as defined above and R₂ is a heterocyclic lower-alkyl ringsystem selected from the group consisting of pyrrolyl lower-alkyl,pyrazolyl lower-alkyl, imidazolyl lower-alkyl, imidazolyllower-thioalkyl, triazolyl lower-alkyl, triazolyl lower-thioalkyl,tetrazolyl lower-alkyl, tetrazolyl lower-thioalkyl, thienyllower-oxyalkyl, thienyl lower-hydroxyalkyl, thien-3-yl lower-alkyl,furanyl lower-hydroxyalkyl, thiazolyl lower-alkyl, oxazolyl lower-alkyl,thiadiazolyl lower-alkyl, oxadiazolyl lower-alkyl, piperidinyllower-alkyl, pyrimidinyl lower-alkyl, pyridazinyl lower-alkyl, triazinyllower-alkyl, indolyl lower-alkyl, isoindolyl lower-alkyl, benzimidazolyllower-alkyl, benzopyrazolyl lower-alkyl, benzoxazolyl lower-alkyl,benzopyranyl lower-alkyl, benzodioxanyl lower-alkyl, benzothiazinyllower-alkyl, quinazolinyl lower-alkyl, purinyl lower-alkyl,naphthalenecarboxamidyl lower-alkyl, and naphthalenesulfamidyllower-alkyl.

In a preferred embodiment, the heterocyclic lower-alkyl ring system isselected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, triazol-3-yl lower-thioalkyl, tetrazol-2-yllower-alkyl, tetrazol-5-yl lower-thioalkyl, thien-2-yl lower-oxyalkyl,thien-2-yl lower-hydroxyalkyl, thien-3-yl lower-alkyl, furan-2-yllower-hydroxyalkyl, thiazol-5-yl lower-alkyl, oxazol-3-yl lower-alkyl,thiadiazol-2-yl lower-alkyl, oxadiazol-3-yl lower-alkyl, piperidin-1-yllower-alkyl, pyrimidin-1-yl lower-alkyl, pyridazin-1-yl, lower-alkyl,triazin-1-yl lower-alkyl, indol-1-yl lower-alkyl, isoindol-2-yllower-alkyl, benzimidazol-1-yl lower-alkyl, benzimidazol-2-yllower-alkyl, benzopyrazol-3-yl lower-alkyl, benzoxazol-3-yl lower-alkyl,benzopyran-4-yl lower-alkyl, benzopyran-7-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzodioxan-8-yl lower-alkyl,benzothiazin-4-yl lower-alkyl, quinazolin-3-yl lower-alkyl, purin-1-yllower-alkyl, purin-7-yl lower-alkyl, N-naphthalenecarboxamidyllower-alkyl, and N-naphthalenesulfamidyl lower-alkyl.

In a more preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, triazol-3-yl lower-thioalkyl, tetrazol-2-yllower-alkyl, tetrazol-5-yl lower-thioalkyl, furan-2-yllower-hydroxyalkyl, oxazol-3-yl lower-alkyl, thiadiazol-2-yllower-alkyl, oxadiazol-3-yl lower-alkyl, piperidin-1-yl lower-alkyl,pyrimidin-1-yl lower-alkyl, pyridazin-1-yl lower-alkyl, triazin-1-yllower-alkyl, indol-1-yl lower-alkyl, isoindol-2-yl lower-alkyl,benzimidazol-1-yl lower-alkyl, benzimidazol-2-yl lower-alkyl,benzopyrazol-3-yl lower-alkyl, benzoxazol-3-yl lower-alkyl,benzopyran-4-yl lower-alkyl, benzopyran-7-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzodioxan 8-yl lower-alkyl,benzothiazin-4-yl lower-alkyl, quinazolin-3-yl lower-alkyl, purin-1-yllower-alkyl, purin-7-yl lower-alkyl, N-naphthalenecarboxamidyllower-alkyl, and N-naphthalenesulfamidyl lower-alkyl.

The heterocyclic ring may be unsubstituted or substituted, wherein thesubstituent group is selected from the group consisting of .[.halogen,oxygen.]. .Iadd.halo, oxo.Iaddend., hydroxyl, nitro, amino,.[.carbonyl,.]. lower-alkoxy carbonyl, lower-alkyl, lower-cycloalkyl,lower-alkoxy, .[.lower/thioalkyl,.]. halogenated lower-alkyl, aryl,halogenated aryl, heterocyclics, and combinations thereof. In apreferred embodiment, the substituent group is selected from the groupconsisting of fluoro, chloro, iodo, .[.oxygen.]. .Iadd.oxo.Iaddend.,nitro, amino, 171 carbonyl,.]. ethoxy carbonyl, methyl, ethyl,isopropyl, spiroethane, methoxy, .[.thiomethyl,.]. trifluoromethyl,phenyl, morpholinyl and combinations thereof.

The lower-alkyl group is selected from the group consisting of branchedor unbranched-hydrocarbon groups containing from 1 to 7 carbon atoms.The lower-alkyl group may be substituted or unsubstituted, withsubstituent members independently selected from the group consisting of.[.oxygen.]. .Iadd.oxo.Iaddend., hydroxyl, .[.sulfur,.]. andcombinations thereof. In a preferred embodiment, the lower-alkyl groupis a member selected from the group consisting of methyl, ethyl,2-hydroxyethyl, .Iadd.and .Iaddend.2-oxoethyl.[., and 2-thioethyl.]..

R₃ is selected from the group consisting of lower-alkoxy carbonyl andlower-alkoxy methyl. In a preferred embodiment, the R₃ group is selectedfrom the group consisting of methoxy carbonyl and methoxymethyl.

In another preferred embodiment, the compounds of the present inventionhave the general formula: ##STR5## including optically active isomericforms, and the pharmaceutically acceptable acid addition salts thereof,wherein R, and R₁ are as defined above, R₂ is a heterocyclic lower-alkylring system selected from the group consisting of pyrrolyl lower-alkyl,pyrazolyl lower-alkyl, imidazolyl lower-alkyl, imidazolyllower-thioalkyl, triazolyl lower-alkyl, triazolyl lower-thioalkyl,tetrazolyl lower-alkyl, tetrazolyl lower-thioalkyl, thienyllower-oxyalkyl, thienyl lower-hydroxyalkyl, thien-3-yl lower-alkyl,thiazolyl lower-alkyl, oxazolyl lower-alkyl, thiadiazolyl lower-alkyl,oxadiazolyl lower-alkyl, piperidinyl lower-alkyl, pyrimidinyllower-alkyl, pyridazinyl lower-alkyl, triazinyl lower-alkyl, indolyllower-alkyl, isoindolyl lower-alkyl, benzimidazolyl lower-alkyl,benzopyrazolyl lower-alkyl, benzoxazolyl lower-alkyl, benzopyranyllower-alkyl, benzodioxanyl lower-alkyl, benzothiazinyl lower-alkyl,quinazolinyl lower-alkyl, purinyl lower-alkyl, naphthalenecarboxamidyllower-alkyl, and naphthalenesulfamidyl lower-alkyl.

In more preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, tetrazol-2-yl lower-alkyl, tetrazol-5-yllower-thioalkyl, 2-thienyl lower-oxyalkyl, 2-thienyl lower-hydroxyalkyl,thien-3-yl lower-alkyl, thiazol-5-yl lower-alkyl, oxazol-3-yllower-alkyl, thiadiazol-2-yl lower-alkyl, oxadiazol-3-yl lower-alkyl,piperidin-1-yl lower-alkyl, pyrimidin-1-yl lower-alkyl, pyridazin-1-yllower-alkyl, triazin-1-yl lower-alkyl, indol-1-yl lower- alkyl,isoindol-2-yl lower-alkyl, benzimidazol-1-yl lower-alkyl,benzimidazol-2-yl lower-alkyl, benzopyra- zol-3-yl lower-alkyl,benzoxazol-3-yl lower-alkyl, benzopyran-4-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzothiazin-4-yl lower-alkyl,quinazolin-3-yl lower- alkyl, purin-1-yl lower-alkyl, purin-7-yllower-alkyl, N-naphthalenecarboxamidyl lower-alkyl, andN-naphthalenesulfamidyl lower-alkyl.

In a most preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, tetrazol-2-yl lower-alkyl, tetrazol-5-yllower-thioalkyl, oxazol-3-yl lower-alkyl, thiadiazol-2-yl lower-alkyl,oxadiazol-3-yl lower-alkyl, piperidin-1-yl lower-alkyl, pyrimidin-1-yllower-alkyl, pyridazin-1-yl lower-alkyl, triazin-1-yl lower-alkyl,indol-1-yl lower-alkyl, isoindol-2-yl lower-alkyl, benzimidazol-1-yllower-alkyl, benzimidazol-2-yl lower-alkyl, benzopyrazol-3-yllower-alkyl, benzoxazol-3-yl lower-alkyl, benzopyran-4-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzothiazin-4-yl lower-alkyl,quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl, purin-7-yllower-alkyl, N-naphthalenecarboxamidyl lower-alkyl, andN-naphthalenesulfamidyl lower-alkyl.

R₃ is a lower-alkoxy carbonyl group, preferably methoxy carbonyl.

The heterocyclic ring may be unsubstituted or substituted, wherein thesubstituent group is selected from the group consisting of .[.halogen,oxygen.]. .Iadd.halo, oxo.Iaddend., hydroxyl, nitro, amino,.[.carbonyl,.]. lower-alkoxy carbonyl, lower-alkyl, lower-cycloalkyl,lower-alkoxy, .[.lower-thioalkyl,.]. halogenated lower-alkyl, aryl,halogenated aryl, heterocyclics, and combinations thereof. In apreferred embodiment, the substituent group is a member selected fromthe group consisting of fluoro, chloro, iodo, .[.oxygen.]..Iadd.oxo.Iaddend., nitro, amino, .[.carbonyl,.]. ethoxy carbonyl,methyl, ethyl, isopropyl, spiroethane, methoxy, .[.thiomethyl,.].trifluoromethyl, phenyl, morpholinyl and combinations thereof.

The lower-alkyl group is selected from the group consisting of branched-or unbranched-hydrocarbon groups containing from 1 to 7 carbon atoms.The lower-alkyl group may be substituted or unsubstituted, withsubstituent members selected from the group consisting of .[.oxygen.]..Iadd.oxo.Iaddend., hydroxyl, .[.sulfur,.]. and combinations thereof. Ina preferred embodiment, the lower-alkyl group is selected from the groupconsisting of methyl, ethyl, 2-hydroxyethyl, .Iadd.and.Iaddend.2-oxoethyl.[., and 2-thioethyl.]..

In another preferred embodiment, the compounds of the present inventionhave the general formula: ##STR6## including optically active isomericforms, and the pharmaceutically acceptable acid addition salts thereof,wherein R and R₁ are as defined above, R₂ is a heterocyclic lower-akylring system selected from the group consisting of pyrrolyl lower-alkyl,pyrazolyl lower-alkyl, imidazolyl lower-alkyl, imidazolyllower-thioalkyl, triazolyl lower-alkyl, triazolyl lower-thioalkyl,tetrazolyl lower-alkyl, tetrazolyl lower-thioalkyl, thienyllower-oxyalkyl, thienyl lower-hydroxyalkyl, thien-3-yl lower-alkyl,furanyl lower-hydroxyalkyl, thiazolyl lower-alkyl, pyrimidinyllower-alkyl, indolyl lower-alkyl, isoindolyl lower-alkyl, benzimidazolyllower-alkyl, benzopyranyl lower-alkyl, benzodioxanyl lower-alkyl,quinazolinyl lower-alkyl, purinyl lower-alkyl, andnaphthalenecarboxamidyl lower-alkyl.

In a preferred embodiment, the heterocyclic lower-alkyl ring system isselected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, triazol-3-yl lower-thioalkyl, tetrazol-2-yllower-alkyl, tetrazol-5-yl lower-thioalkyl, thien-2-yl lower-oxyalkyl,thien-2-yl lower-hydroxyalkyl, thien-3-yl lower-alkyl, furan-2-yllower-hydroxyalkyl, thiazol-5-yl lower-alkyl, pyrimidin-1-yllower-alkyl, indol-1-yl lower-alkyl, isoindol-2-yl lower-alkyl,benzimidazol-1-yl lower-alkyl, benzoxazol-3-yl lower-alkyl,benzopyran-4-yl lower-alkyl, benzopyran-7-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzodioxan-8-yl lower-alkyl,quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl, purin-7-yllower-alkyl, and N-naphthalenecarboxamidyl lower-alkyl.

In a more preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, triazol-3-yl lower-thioalkyl, tetrazol-2-yllower-alkyl, tetrazol-5-yl lower-thioalkyl, furan-2-yllower-hydroxyalkyl, pyrimidin-1-yl lower-alkyl, indol-1-yl lower-alkyl,isoindol-2-yl lower-alkyl, benzimidazol-1-yl lower-alkyl,benzoxazol-3-yl lower-alkyl, benzopyran-4-yl lower-alkyl,benzopyran-7-yl lower-alkyl, benzodioxan-2-yl lower-alkyl,benzodioxan-8-yl lower-alkyl, quinazolin-3-yl lower-alkyl, purin-1-yllower-alkyl, purin-7-yl lower-alkyl, and N-naphthalenecarboxamidyllower-alkyl.

The heterocyclic ring may be unsubstituted or substituted, wherein thesubstituent group is a member independently selected from the groupconsisting of .[.halogen, oxygen.]. .Iadd.halo, oxo.Iaddend., hydroxyl,nitro, amino, .[.carbonyl,.]. lower-alkoxy carbonyl, lower-alkyl,lower-cycloalkyl, lower-alkoxy, .[.lower-thioalkyl,.]. halogenatedlower-alkyl, aryl, halogenated aryl, heterocyclics, and combinationsthereof. In a preferred embodiment, the substituent group is a memberselected from the group consisting of fluoro, chloro, iodo, .[.oxygen.]..Iadd.oxo.Iaddend., nitro, amino, .[.carbonyl,.]. ethoxy carbonyl,methyl, ethyl, isopropyl, spiroethane, methoxy, .[.thiomethyl,.].trifluoromethyl, phenyl, morpholinyl and combinations thereof.

The lower-alkyl group is a member selected from the group consisting ofbranched or unbranched hydrocarbon groups containing from 1 to 7 carbonatoms. The lower-alkyl group may be substituted or unsubstituted, withsubstituent members independently selected from the group consisting of.[.oxygen.]. .Iadd.oxo.Iaddend., hydroxyl, .[.sulfur,.]. andcombinations thereof. In a preferred embodiment, the lower-alkyl groupis a member selected from the group consisting of methyl, ethyl,2-hydroxyethyl, .Iadd.and .Iaddend.2-oxoethyl.[., and 2-thioethyl.]..

R₃ is a lower-alkoxy methyl group. In a preferred embodiment, the R₃group is methoxymethyl.

In another preferred embodiment, the compounds of the present inventionhave the general formula: ##STR7## including optically active isomericforms, and the pharmaceutically acceptable acid addition salts thereofwherein:

R is a n aryl group selected from the group consisting of phenyl andsubstituted phenyl, wherein said substituents are selected from thegroup consisting of halogen, lower-alkoxy, and combinations thereof.Preferred substituents are fluoro or methoxy. The preferred position forattachment of a substituent to the phenyl ring is at the 2 (ortho)position. In a preferred embodiment, R is selected from the groupconsisting of phenyl, 2-fluorophenyl and 2-methoxyphenyl. In a morepreferred embodiment, R is 2-fluorophenyl or 2-methoxyphenyl.

R₁ is selected from the group consisting of lower-alkyl, lower-alkenyl,lower-alkyl and lower-alkoxy having from 2 to 6 carbon atoms. In apreferred embodiment, R₁ is selected from the group consisting of ethyl,ethenyl, methoxymethyl and 1-methoxyethyl.

R₂ is a heterocyclic lower-alkyl ring system selected from the groupconsisting of pyrazolyl lower-alkyl, imidazolyl lower-alkyl,imidazolinyl lower-alkyl, benzimidazolyl lower-alkyl, and phthalimidyllower-alkyl. In a preferred embodiment, the heterocyclic lower-alkylring system is selected from the group consisting of pyrazol-1-yllower-alkyl, imidazol-1-yl lower-alkyl, imidazolin-1-yl lower-alkyl,benzimidazol-1-yl lower-alkyl, and N-phthalimidyl lower-alkyl.

The heterocyclic ring may be unsubstituted or substituted, wherein saidsubstituents are selected from the group consisting of .[.halogen,oxygen.]. .Iadd.halo, oxo.Iaddend., hydroxyl, nitro, amino,.[.carbonyl,.]. lower-alkoxy carbonyl, lower-alkyl, lower-cycloalkyl,lower-alkoxy, .[.lower/thioalkyl,.]. halogenated lower-alkyl, aryl,halogenated aryl, heterocyclics, and combinations thereof. In apreferred embodiment, the substituents are selected from the groupconsisting of fluoro, chloro, iodo, .[.oxygen.]. .Iadd.oxo.Iaddend.,nitro, amino, carbonyl, ethoxy, carbonyl, methyl, ethyl, isopropyl,spiroethane, methoxy, .[.thiomethyl,.]. trifluoromethyl, phenyl,halogenated aryl, morpholinyl and combinations thereof. In a morepreferred embodiment, the substituents are selected from the groupconsisting of methyl, ethyl, nitro, halogenated aryl and combinationsthereof.

The lower-alkyl group is branched- or unbranched-hydrocarbon groupcontaining from 1 to 7 carbon atoms. The lower-alkyl group may besubstituted or unsubstituted, with substituents being selected from thegroup consisting of .[.oxygen.]. .Iadd.oxo.Iaddend., hydroxyl,.[.sulfur,.]. and combinations thereof. In a preferred embodiment, thelower-alkyl group is selected from the group consisting of methyl,ethyl, 2-hydroxyethyl, .Iadd.and .Iaddend.2-oxoethyl, .[.and2-thioethyl,.]. most preferably an ethyl group.

R₃ is selected from the group consisting of lower-alkoxy carbonyl andlower-alkoxy methyl. In a preferred embodiment, the R₃ group is a memberselected from the group consisting of methoxy carbonyl andmethoxymethyl.

In another preferred embodiment, the compounds of the present inventionhave the general formula: ##STR8## including optically active isomericforms, and the pharmaceutically acceptable acid addition salts thereof,wherein:

R is an aryl group selected from the group consisting of phenylsubstituted phenyl, wherein said substituents are selected from thegroup consisting of .[.halogen.]. .Iadd.halo.Iaddend., lower-alkoxy, andcombinations thereof. Preferred substituents are fluoro and methoxy. Thepreferred position for attachment of a substituent to the phenyl ring isat the 2 (ortho) position. In a preferred embodiment, R is selected fromthe group consisting of phenyl, 2-fluorophenyl and 2-methoxyphenyl, mostpreferably, 2-fluorophenyl.

R₁ is selected from the group consisting of lower-alkyl, lower-alkenyl,and lower-alkoxy lower-alkyl having from 2 to 6 carbon atoms. In apreferred embodiment, R₁ is selected from the group consisting of ethyl,ethenyl, methoxymethyl and 1-methoxyethyl. In a more preferredembodiment, R₁ is ethyl and methoxymethyl.

R₂ is a heterocyclic lower-alkyl ring system selected from the groupconsisting of pyrrolyl lower-alkyl, pyrazolyl lower-alkyl, imidazolyllower-alkyl, imidazolyl lower-thioalkyl, triazolyl lower-alkyl,triazolyl lower-thioalkyl, tetrazolyl lower-alkyl, tetrazolyl lowerthioalkyl, thienyl lower-oxyalkyl, thienyl lower-hydroxyalkyl,thien-3-yl lower-alkyl, furanyl lower-hydroxyalkyl, thiazolyllower-alkyl, oxazolyl lower-alkyl, thiadiazolyl lower-alkyl, oxadiazolyllower-alkyl, piperidinyl lower-alkyl, pyrimidinyl lower-alkyl,pyridazinyl lower-alkyl, triazinyl lower-alkyl, indolyl lower alkyl,isoindolyl lower-alkyl, benzimidazolyl lower-alkyl, benzopyrazolyllower-alkyl, benzoxazolyl lower-alkyl, benzopyranyl lower-alkyl,benzodioxanyl lower-alkyl, benzothiazinyl lower-alkyl, quinazolinyllower-alkyl, purinyl lower- alkyl, naphthalenecarboxamidyl lower-alkyl,and naphthalenesulfamidyl lower-alkyl.

In a preferred embodiment, the heterocyclic lower-alkyl ring system isselected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, triazol-3-yl lower-thioalkyl, tetrazol-2-yllower-alkyl, tetrazol-5-yl lower-thioalkyl, thien-2-yl, lower-oxyalkyl,thien-2-yl lower-hydroxyalkyl, thien-3-yl lower-alkyl, furan-2-yllower-hydroxyalkyl, thiazol-5-yl lower-alkyl, oxazol-3-yl lower-alkyl,thiadiazol-2-yl lower-alkyl, oxadiazol-3-yl lower-alkyl, piperidin-1-yllower-alkyl, pyrimidin-1-yl lower-alkyl, pyridazin-1-yl lower-alkyl,triazin-1-yl lower-alkyl, indol-1-yl lower-alkyl, isoindol-2-yllower-alkyl, benzimidazol-1-yl lower-alkyl, benzimidazol-2-yllower-alkyl, benzopyrazol-3-yl lower-alkyl, benzoxazol-3-yl lower-alkyl,benzopyran-4-yl lower-alkyl, benzopyran-7-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzodioxan-8-yl lower-alkyl,benzothiazin-4-yl lower-alkyl, quinazolin-3-yl lower-alkyl, purin-1-yllower-alkyl, purin-7-yl lower-alkyl, N-naphthalenecarboxamidyllower-alkyl, and N-naphthalenesulfamidyl lower-alkyl.

In a more preferred embodiment, the heterocyclic lower-alkyl ring systemis selected from the group consisting of pyrrol-1-yl lower-alkyl,pyrazol-1-yl lower-alkyl, imidazol-1-yl lower-alkyl, imidazol-3-yllower-alkyl, imidazol-4-yl lower-alkyl, imidazol-2-yl lower-thioalkyl,triazol-1-yl lower-alkyl, triazol-3-yl lower-thioalkyl, tetrazol-2-yllower-alkyl, tetrazol-5-yl lower-thioalkyl, thien-2-yl lower-oxyalkyl,thien-2-yl lower-hydroxyalkyl, thien-3-yl lower-alkyl, furan-2-yllower-hydroxyalkyl, thiazol-5-yl lower-alkyl, oxazol-3-yl lower-alkyl,thiadiazol-2-yl lower-alkyl, oxadiazol-3-yl lower-alkyl, piperidin-1-yllower-alkyl, pyrimidin-1-yl lower-alkyl, pyridazin-1-yl lower-alkyl,triazin-1-yl lower-alkyl, indol-1-yl lower-alkyl, isoindol-2-yllower-alkyl, benzimidazol-1-yl lower-alkyl, benzimidazol-2-yllower-alkyl, benzopyrazol-3-yl lower-alkyl, benzoxazol-3-yl lower-alkyl,benzopyran-4-yl lower-alkyl, benzopyran-7-yl lower-alkyl,benzodioxan-2-yl lower-alkyl, benzodioxan-8-yl lower-alkyl,benzothiazin-4-yl lower-alkyl, quinazolin-3-yl lower-alkyl, purin-1-yllower-alkyl, purin-7-yl lower-alkyl, N-naphthalenecarboxamidyllower-alkyl, and N-naphthalenesulfamidyl lower-alkyl.

In a most preferred embodiment, the R₂ group is a heterocycliclower-alkyl ring system selected from the group consisting of pyrazolyllower-alkyl, tetrazolyl lower-alkyl, isoindolyl lower-alkyl, andbenzimidazolyl lower-alkyl.

In another preferred embodiment, the heterocyclic lower-alkyl ringsystem is selected from the group consisting of pyrazol-1-yllower-alkyl, tetrazol-1-yl lower-alkyl, tetrazol-2-yl lower-alkyl,isoindol-2-yl lower-alkyl, benzimidazol-1-yl lower-alkyl, andbenzimidazol-2-yl lower-alkyl.

The heterocyclic ring may be unsubstituted or substituted, wherein thesubstituents are selected from the group consisting of .[.halogen,oxygen.]. .Iadd.halo, oxo.Iaddend., hydroxyl, nitro, amino,.[.carbonyl,.]. lower-alkoxy carbonyl, lower-alkyl, lower-cycloalkyl,lower-alkoxy, .[.lower-thioalkyl,.]. halogenated lower-alkyl, aryl,halogenated aryl, heterocyclics, and combinations thereof. In apreferred embodiment, the substituent group is selected from the groupconsisting of fluoro, chloro, iodo, .[.oxygen.]. .Iadd.oxo.Iaddend.,nitro, amino, .[.carbonyl,.]. ethoxy carbonyl, methyl, ethyl, isopropyl,spiroethane, methoxy, .[.thiomethyl,.]. trifluoromethyl, phenyl,halogenated aryl, morpholinyl and combinations thereof. In a morepreferred embodiment, the substituent group is selected from the groupconsisting of methyl, ethyl, nitro, halogenated aryl and combinationsthereof.

The lower-alkyl group is a branched- or unbranched-hydrocarboncontaining from 1 to 7 carbon atoms. The lower-alkyl group may besubstituted or unsubstituted, with substituents being selected from thegroup consisting of .[.oxygen.]. .Iadd.oxo.Iaddend., hydroxyl,.[.sulfur,.]. and combinations thereof. In a preferred embodiment, thelower-alkyl group is selected from the group consisting of methyl,ethyl, 2-hydroxyethyl, .Iadd.and .Iaddend.2-oxoethyl.[., and2-thioethyl.].. In a more preferred embodiment, the lower-alkyl group ismethyl or ethyl.

R₄ is methyl.

The term "lower-alkyl", as used herein, means branched- orunbranched-hydrocarbon groups containing from 1 to 7 carbon atoms. Theterm "lower-alkoxy", as used herein, means branched- orunbranched-hydrocarboxy groups containing from 1 to 7 carbon atoms. Theterm "lower-cycloalkyl", as used herein, means cyclic alkyl groupscontaining from 3 to 6 carbon atoms. Preferred heterocyclic groupsinclude from 6 to 12 carbon atoms and can include the substituentsdiscussed above in connection with heterocyclic groups. The term"halogen", as used herein, refers to the chemically related elementsfluorine, chlorine, bromine and iodine.

The compounds of the present invention which have at least oneasymmetric carbon atom can exist in optically active isomeric forms. Forexample, in compounds in which R₂ is a 2-phenyl-1-propyl or1-phenyl-2-propyl group, etc., the carbon adjacent to the piperidinylnitrogen is an asymmetric carbon atom and such compounds can thereforeexist in optical active isomeric (enantiomeric) forms. Such isomericforms can be isolated from the racemic mixtures by techniques known tothose skilled in the art.

The compounds of the present invention which have an alkyl group as theR₄ group exist in cis or trans form. Such compounds can be used as amixture of such forms but many times one form is more active than theother or has other desirable characteristics. Thus, many times it isdesirable to resolve the cis/trans mixture. This resolution can beaccomplished by techniques conventional in the art for such purpose,e.g., chromatographic techniques such as column chromatography or highpressure liquid chromatography or simple recrystallization techniques.

The compounds of the present invention can be prepared by variousmethods. In general, the desired compounds having Formulae I, II or IIIabove can be prepared by reacting a compound having the formula ##STR9##with a compound having the formula:

    R.sub.1 --CO--X or (R.sub.1 CO).sub.2 O

or by reacting a compound having the formula: ##STR10## with a compoundhaving the formula:

    R.sub.2 X

wherein the substituent groups R, R₁, R₂, R₃ and R₄ have the definitionsset out above, and X represents halide or its reactive equivalent.Examples of halide reactive equivalents are toluene sulfonate, phenylsulfonate, methyl sulfonate and the like.

In the first reaction, when the R₂ group is phenylmethyl (benzyl), thephenylmethyl group can be cleaved by hydrogenolysis or by reaction with1-chloroethyl chloroformate followed by hydrolysis with methanol, see R.A. Olofson et al., J. Org. Chem., 49, pp. 2081-2082 (1984), and replacedwith other R₂ groups such as furanyl lower-alkyl, pyrazoyl lower-alkyland the like. The preparation of secondary amines of the latter type hasbeen described by P. G. H. Van Daele et al., Arzneim-Forsch. Drug Res.,26, p. 1521, (1976).

Several convenient routes for the preparation of the compounds of theinvention begin with known piperidone starting materials as shown below:##STR11##

The compound 1-(2-phenylethyl)-4-piperidone (1), when R₃ ═H, or1-(2-phenylethyl)-3-methyl-4-piperidone (1), when R₃ ═CH₃, can beprepared according to the procedure published by A. H. Becket, A. F.Casey and G. Kirk, J. Med Pharm. Chem., Vol. 1, p. 37 (1959. Thecompound 1-phenylmethyl-4-piperidone (2), when R3═H, or1-phenylmethyl-3-methyl-4-piperidone (2), when R₃ ═CH₃, can be preparedin an analogous manner by the procedure described by C. R. Ganellin andR. G. Spickch, J. Med. Chem., Vol. 8, p. 619 (1965) or P. M. Carabateasand L. Grumbach, J. Med. Pharm. Chem., Vol. 5, p. 913 (1962).

In one example of a method for preparing the compounds of the presentinvention, 1-phenylmethyl or 1 (2-phenylethyl)-4-piperidone is reactedwith an unsubstituted or substituted heterocyclic amine to form a Schiffbase. The Schiff base is then reduced, for example, with sodiumborohydride to yield the unsubstituted or substituted 1-phenylmethyl or1-(2-phenylethyl)-4-(N-heterocycloamine)-piperidine compound. See forexample, S. Grossman et al., Arch. Pharm. (Weinheim) 311, p. 1010(1978). The following reaction scheme, wherein R is a heterocyclic groupwithin the definition of the present invention, illustrates such amethod: ##STR12##

When the R₄ group is hydrogen, compound (3) can be reacted with anappropriate acid halide (e.g., R₁ COCl) or an anhydride (e.g., (R₁ CO)₂O) to introduce the desired R₁ -carbonyl group on the nitrogen atom andthereby obtain compound (I) of the present invention, according to thereaction scheme shown below: ##STR13##

When the R₄ group is methyl, cis and trans isomers of compound (3) arecreated. The cis and trans isomers can be separated before or afterreaction with an acid halide or anhydride, as set out above, therebyobtaining cis and trans isomers of compound (I) of the presentinvention. Separation of the cis/trans isomers can be carried outaccording to the following reaction scheme: ##STR14##

When the desired R₂ substituent group is not phenylethyl, one procedurefor preparing compounds of the present invention with different R₂groups is to remove the phenylmethyl group in compound (2) byhydrogenolysis (for example, using hydrogen over 10% palladium oncarbon) or by reaction with 1-chloroethyl chloroformate above andreplace it with a desired R₂ group. For example, compounds of theinvention can be prepared according to the following scheme: ##STR15##

As set out above, when the R₄ group is methyl, compound (4) is a mixtureof cis and trans isomers which can be separated prior to the next step.When the R₄ groups is hydrogen, no preliminary cis/trans isomerseparation is necessary. After any such cis/trans separation, compound(4) can be reacted with hydrogen over palladium on carbon or with1-chloroethyl chloroformate according to the following reaction schemeto remove the phenylmethyl group and prepare piperidinyl intermediate(5): ##STR16##

The desired R₂ substituent group can then be introduced by reactingcompound (5) with an appropriately reactive molecule R₂ -X, wherein X ishalogen, such as chlorine, bromine, or iodine, or its reactiveequivalent, to obtain compound (I) of the present invention according tothe reaction scheme illustrated below: ##STR17##

The reaction of R₂ -X with a piperdinyl intermediate such as compound(5) can be conducted in an inert organic solvent such as, for example,an aromatic hydrocarbon, a ketone such as 4-methyl-2-pentanone and thelike, an ether such as 1,4-dioxane, diethylether, tetrahydofuran,1,2-dimethoxyethane and the like, or N,N-dimethylformamide oracetonitrile. The addition of an appropriate base, such as an alkalimetal carbonate, may be utilized to neutralize the acid generated duringthe reaction. The addition of an iodide salt, such as an alkali metaliodide, may be appropriate. The temperature of the reaction mixture maybe raised to increase the rate of reaction when appropriate.

In an alternative procedure, the phenylmethyl group can first be removedby hydrogenolysis or by reaction with 1-chloroethyl chloroformate priorto separation of the cis/trans isomers of compound (4) to obtaincompound (I) of the present invention with the R₁ and R₂ groupsintroduced according to one of the two schemes shown below: ##STR18##

In a second example of a method for preparing the compounds of thepresent invention, an intermediate such asN-(phenylethyl)-4-piperidineamine (6) is utilized. In this method, theprimary amine is reacted with a heterocycle group RX, where X is ahalide or its reactive equivalent, to form a secondary amine precursor(7). The secondary amine is then acrylated. See, for example, Y. Zhu etal., Acta Pharm. Sinica, 16, p. 199 (1981). The following reactionscheme, wherein R is a heterocyclic group within the definition of thepresent invention, illustrates such a method to make compound (I) of thepresent invention. ##STR19##

In a third example of a method for preparing the compounds of thepresent invention, the same intermediate, such asN-(phenylethyl)-4-piperidineamine (6), is utilized. In this method, theprimary amine is reacted with an oxo-derivative of the heterocycle groupR to form a secondary amine precursor. The oxo-intermediate is reducedprior to acylation. See, for example, Langhein et al.,Offenlegungschrift, 234, p. 1965 (1975); Chem. Abstr. 82, 156121w(1975).

Compounds of the present invention which have 4,4-disubstitution can beprepared starting with, for example, N-phenylmethyl-4-piperidone by thefollowing reaction scheme: ##STR20##

The compounds of the present invention while effective in the form ofthe free base may be formulated and administered in the form of thetherapeutically or pharmaceutically acceptable acid addition salts forpurposes of stability, convenience Of crystallization, increasedsolubility and the like. These acid addition salts include inorganicacid salts such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric, perchloric acid salts and the like; and organic acid saltssuch as acetic, trifluoroacetic, propionic, oxalic, hydroxyacetic, meth-oxyacetic, 2-hydroxypropanoic, 2/oxopropanoic, propanedioic,2-hydroxy-butanedioic, benzoic, 2-hydroxybenzoic,4-amino-2-hydroxy-benzoic, 3/phenyl-2-propenoic,alpha-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,benzenesulfonic, toluene-sulfonic, cyclohexanesulfamic, succinic,tartaric, citric, maleic, fumaric acid salts and the like. The preferredacid addition salts are chloride, oxalate and citrate. These acidaddition salts can be prepared by conventional methods, such as bytreatment of the free base of the inventive compound with theappropriate acid.

The compounds of the present invention, prepared in the free base form,can be combined with a pharmaceutically acceptable carrier to provide apharmaceutical composition. Suitable carriers for the free bases includepropylene glycol-alcohol-water, isotonic water, sterile water forinjection (USP), emulphor ™-alcohol-water, cremophor-EL ™ or othersuitable carriers known to those skilled in the art.

The compounds of the present invention, prepared in the pharmaceuticallyacceptable acid addition salt form, can also be combined with apharmaceutically acceptable carrier to provide a pharmaceuticalcomposition. Suitable carriers for the acid addition salts includeisotonic water, sterile water for injection (USP), alone or incombination with other solubilizing agents such as ethanol, propyleneglycol, or other conventional solubilizing agents known to those skilledin the art.

Of course, the type of carrier will vary depending upon the mode ofadministration desired for the pharmaceutical composition as isconventional in the art. A preferred carrier is an isotonic aqueoussolution of the inventive compound.

The compounds of the present invention can be administered to mammals,e.g., animals or humans, in amounts effective to provide the desiredanalgesic therapeutic effect or to reverse the actions of an opiateanalgesic. Since the activity of the compounds and the degree of thedesired therapeutic effect vary, the dosage level of the compoundemployed will also vary. The actual dosage administered will also bedetermined by such generally recognized factors as the body weight ofthe patient and the individual hypersensitiveness of the particularpatient. Thus, the unit dosage for a particular patient (man) can be aslow as about 0.00005 mg/kg, which the practitioner may titrate to thedesired effect.

The compounds of the present invention can be administered parenterally,in the form of sterile solutions or suspensions, such as intravenously,intramuscularly or subcutaneously in the carriers previously described.The compounds may also be administered orally, in the form of pills,tablets, capsules, troches, and the like, as well as sublingually,rectally, or transcutaneously with a suitable pharmaceuticallyacceptable carrier for that particular mode of administration as isconventional in the art.

For parental therapeutic administration, the compounds of the presentinvention may be incorporated into a sterile solution or suspension.These preparations should contain at least about 0.1% of the inventivecompound, by weight, but this amount may be varied to between about 0.1%and about 50% of the inventive compound, by weight of the parentalcomposition. The exact amount of the inventive compound present in suchcompositions is such that a suitable dosage level will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a paranteral dosage unit contains frombetween about 0.5 to about 100 milligrams of the inventive compound.

The sterile solutions or suspensions may also include the followingadjuvants: a sterile diluent, such as water for injection, salinesolution, fixed oils, polyethylene glycol, glycerine, propylene glycol,or other synthetic solvent; antibacterial agents, such as benzyl alcoholor methyl paraben; antioxidants, such as ascorbic acid or sodiummetabisulfite; chelating agents, such as ethylenediaminetetraacetic acid(EDTA); buffers, such as acetates, citrates or phosphates; and agentsfor the adjustment of tonicity, such as sodium chloride or dextrose. Theparental preparations may be enclosed in ampules, diposable syringes, ormultiple dose vials made of glass or plastic.

The compounds of the present invention can also be administered orally.For oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, capsules, elixirs,suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least about 4% of the inventive compound,by weight, but this amount may be varied depending upon the particulardosage form from between about 4% to about 70% of the inventivecompound, by weight of the oral composition. The exact amount of thecompound present in the composition is such that a suitable dosage willbe obtained. Preferred compositions and preparations according to thepresent invention are prepared so that an oral dosage unit form containsfrom between about 5 to about 300 milligrams of the inventive compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder, such as microcrystalline cellulose, gumtragacanth or gelatine; an excipient, such as starch or lactose; adisintegrating agent, such as alginic acid, Primogel, corn starch andthe like; a lubricating agent, such as magnesium stearate or Sterotex; agliding agent, such as colloidal silicon dioxide; a sweetening agent,such as sucrose or saccharin; and a flavoring agent, such as peppermint,methyl salicylate or orange flavoring. When the dosage form is acapsule, it may additionally contain a liquid carrier such as a fattyoil. Other dosage unit forms may contain other materials which modifythe physical form of the dosage unit, such as enteric coatings. Thustablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the above adjuvants,sucrose as a sweetening agent, preservatives, dyes, coloring agents andflavoring agents.

It is especially advantageous to formulate the pharmaceuticalcompositions in dosage unit forms for ease of administration anduniformity of dosage. The term dosage unit forms a used herein refers tophysically discrete units suitable for use as a unitary dosage, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with thepharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

The present invention is further illustrated by the following exampleswhich are presented for purposes of demonstrating, but not limiting, thepreparation of the compounds and compositions of this invention.

EXAMPLE 1

This Example illustrates the preparation of secondary amine intermediatecompounds.

The preparation of secondary amine intermediate compounds of type (9)having the general formula: ##STR21## wherein the substituent groups R,R₁, R₃, and R₄ have the definitions set out above, has been describedin, for example, U.S. Pat. No. 4,584,303, P. G. H. Van Daele et al.,Arzneim-Forsch. Drug Res., 26 p. 1521, (1976).

EXAMPLE 2

This Example illustrates the preparation of heterocyclic alkylelectrophile intermediate compounds.

The compounds of the present invention were prepared essentially byreacting secondary amine intermediate compounds of type (9) from Example1 with an appropriate heterocyclic alkyl electrophile intermediatecompound of type (10) having the formula:

    R.sub.2 X                                                  (10)

wherein the substituent group R₂ has the definition set out above and Xis a halide or its reactive equivalent.

The heterocyclic alkyl electrophile intermediates of type (10) which arecommercially available include 3-(2-chloroethyl)-2-oxazolinone (AldrichChemical Company, Inc. Milwaukee, Wis., "Aldrich"), 4-vinylpyridine(Aldrich), 3-(dimethylaminomethyl)indole (Aldrich),N-(2-bromoethyl)phthalimide (Aldrich), 2-(chloromethyl)-benzimidazole(Aldrich), 4-(bromomethyl)-7-methoxycoumarin (Aldrich,8-chloromethyl-2-fluorobenzo-1,3-dioxane (Maybridge Chemical CompanyLtd., Trevillett, Tintagel, Cornwall TL34 OHW United Kingdom,"Maybridge"), 3-(2-bromoethyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Maybridge), 7-(2-chloroethyl)theophylline (Aldrich), andN-(2-chloroethyl-1,8-naphthalimide (Aldrich).

EXAMPLE 3

This Example illustrates the preparation of heterocyclic alkylelectrophile intermediate compounds.

The heterocyclic alkyl electrophile intermediates of type (10) which areavailable from previously published procedures include1-(2-chloroethyl)-1H-pyrrole (Machin et al., J. Med. Chem., 1984, 27, p.508), 1-(2-tosylethyl)-1H-pyrazole (Carpio et al., Can. J. Chem., 1982,60, p. 2295, 1-(2-chloroethyl)-1H-imidazole hydrochloride (Thomas etal., B. Ger. Offen. DE 3,438,919, 1986),5-nitro-1-(2-chloroethyl)-1H-imidazole (Caplav et al., Acta. Pharm.Jugosl., 1975, 25, p. 71,2-methyl-5-nitro-1-(2-chloroethyl)-1H-imidazole (Alcalde et al., J.Heterocyclic Chem., 1984, 21, p. 1647), 4-(2-chloroethyl)-1H-imidazolehydrochloride (Turner et al., J. Amer. Chem. Soc. 1949, 71, p. 3476, thealcohol precursor for 4-(2-chloroethyl)imidazole hydrochloride wasconveniently provided by the procedure of Hirsch et al., J. Appl. Chem.,1969, 19, p. 83), 1-methyl-2-(2-chloroethylthio)-1H-imidazole (Tweit, R.C. Ger. Offen. DE 2348525, 1978; Chem. Abstr., 1974, 81, 63626b),2-(bromoacetyl)-thiophene (Kipnis et al., J. Amer. Chem. Soc., 1949, 71,p. 10), 2-(bromoacetyl)furan (Loiseau et al., Eur. J. Chem., 1987, 22,p. 457), 5-methyl-2-chloroacetylfuran (Best et al., Tetrahedron Lett.,1981, 22, p. 4877),1-(2-bromoethyl)-3-methyl-4-amino-5-(1H)-triazolinone (Malbec et al., J.Heterocyclic Chem., 1984, 21, p. 1769),3-methyl-1-(2-bromoethyl)-1,6-dihydro-1H-pyridazin-6-one (Toshihiro etal., J. Med. Chem., 1982, 25, p. 975),1-(2-chloroethyl)-1H-benzimidazole (Pozharski et al., Khim. Geterotsikl.Soedin, 1969, p. 869; Chem. Abstr., 1969, 72, 111370b),(1'-(2-bromoethyl)spiro-cyclopropane)-1,3'-[3H]-indole-2'-(1'H)-one(Robertson et al., J. Med. Chem., 1987, 30, p. 824)6-(2-bromoacetyl)-1,3-benzoxazolin-2-one (Vaccher-Ledein et al., Bull.Soc. Pharm. Lille. 1981, 37, p. 89), 7-(2-bromoethoxy)coumarin (Abyshevet al., Khim.-Farm. Zh., 1985, 19, p. 756; Chem. Abstr., 1985, 103,13435g), and 2-methyl-3-(2-chloro-ethyl)-3,4-dihydroquinazolin-4-one(Singh, P., J. Indian Chem., 1978, 55, p. 801).

EXAMPLE 4

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

The heterocyclic alkyl electrophile intermediates of type (10), when notcommercially available, were generally synthesized by three routes ofalkylation. These routes include substitution of an appropriateheterocyclic intermediate with 2-bromochloroethane or 1,2-dibromoethanein (1) sodium ethoxide-ethanol, (2) sodium hydride-dimethylformamide, or(3) quaternary ammonium phase transfer medium. A few procedures includedalkylation of a peripheral thio group. The alcohol intermediates wereactivated by tosylation or chlorination with thionyl chloride.

The heterocyclic alkyl electrophile intermediates were generallyworked-up in the following manner. The reaction medium was concentratedunder vacuum, the crude concentrate was partitioned between methylenechloride (CH₂ Cl₂) or chloroform (CHCl₃) (50 ml) and water (50 ml), theaqueous layer was extracted with additional organic solvent, thecombined organic extracts were washed with water (50 ml), brine (30 ml),and the organic layer was dried over sodium sulfate (Na₂ SO₄).

The heterocyclic alkyl electrophile intermediates of type (10) wereusually purified by column chromatography using the following solventsystems:

A=chloroform;

B=chloroform-methanol-triethylamine, 19:1:0.1;

C=chloroform-methanol-triethylamine, 80:1:0.1;

D=chloroform-methanol, 19:1; E=chloroform-methanol, 40:1;

F=hexane-ethyl acetate-triethylamine, 4:1:0.1;

G=hexane-ethyl acetate-triethylamine, 5:1:0.1;

H=hexane-ethyl acetate-triethylamine, 5:5:0.1;

I=hexane-ethyl acetate-ammonium hydroxide, 3:1:0.1;

J=hexane-ethyl acetate, 1:1;

K=hexane-ethyl acetate, 3:1;

L=hexane-ethyl acetate, 7:1.

The purity of the heterocyclic alkyl electrophile intermediates wasconfirmed by thin layer chromatography (TLC) analysis. The structure ofthe heterocyclic alkyl electrophile intermediates was confirmed by ¹ HNMR analysis wherein the characteristic resonances of the heterocyclicmoiety were compared to the characteristic resonances of the immediateprecursor. Usually two prominent triplets were observed at approximately3.70 ppm (heterocycle-CH₂ CH₂ X) and at approximately 4.20 ppm(heterocycle-CH₂ CH₂ X). These heterocyclic alkyl electrophileintermediates were used directly in the synthesis of the compounds ofthe present invention without further characterization.

The pertinent data for each heterocyclic alkyl electrophile intermediateis presented below in the following format after each general method:(heterocyclic alkyl electrophile precursor, source of precursor, %yield, letter designation for column chromatography solvent system).

Sodium pieces (0.79 g, 34.3 mmol were dissolved in absolute ethanol (150ml and the resulting solution was cooled to room temperature. A quantityof 3,5-diethoxycarbonyl-1H-pyrazole (7.3 g, 34.3 mmol, Makabe et al.,Bull. Chem. Soc. Jpn., 1975, 48, p. 3210) was added in one portion tothe solution and the reaction mixture was stirred at room temperaturefor 20 minutes. A quantity of 1,2-dibromoethane (34.3 ml, 69.6 mmol) wasthen added to the solution in one portion and the reaction mixture washeated under reflux for 24 hours. The reaction mixture was then cooledand concentrated under vacuum and the residue worked-up as describedabove. The intermediate was purified by column chromatography 400 g finesilica; chloroform-methanol, 40:1) to yield 3.9 g (31%) of2-(3,5-diethoxycarbonyl)-1H-pyrazol-1-yl ethyl) bromide.

EXAMPLE 5

The Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

When an equivalent amount of 4,5-diethoxycarbonyl-1H-imidazole issubstituted for 3,5-diethoxycarbonyl-1H-pyrazole in the procedure ofExample 4, 2-(4,5-diethoxycarbonyl-1H-imidazole-1-yl)ethyl bromide isisolated after column chromatography (4,5-diethoxycarbonyl-1H-imidazole,Bauer et al., Heterocyclic Chem., 1964, 1, p. 275, 52%, D).

EXAMPLE 6

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

When an equivalent amount of 1,2,4-triazole is substituted for3,5-diethoxycarbonyl-1H-pyrazole and an equivalent amount of2-bromochloroethane is substituted for 1,2-dibromoethane in theprocedure of Example 4, 2-H-triazol-1-yl)ethyl chloride is isolated1,2,4-triazole, Aldrich, 43%, used directly after workup).

EXAMPLE 7

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compound in sodium ethoxide in ethanol.

When the equivalent amount of 5-phenyl-2H-tetrazole is substituted for3,5-diethoxycarbonyl-1H-pyrazole and an equivalent amount of2-bromochloroethane is substituted for 1,2-dibromoethane in theprocedure of Example 4, 2-(5-phenyl-2H-tetrazole)ethyl chloride isisolated after column chromatography (5-phenyl-2H-tetrazole, Gump etal., U.S. Pat. No. 2,533,243; Chem. Abstr. 1950, 45, 4271c, 48% fromethanol, mp. 52°-56° C.)

EXAMPLE 8

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

When an equivalent amount of 5-(1-morpholinyl)-2H-tetrazole issubstituted for 3,5-diethoxycarbonyl-1H-pyrazole and an equivalentamount of 2-bromochloroethane is substituted for 1,2-dibromoethane inthe procedure of Example 4, 2-(5-(1-morpholinyl-2H-tetrazol-2-yl)ethylchloride is isolated after column chromatography(5-(1-morpholinyl)-2H-tetrazole, Maybridge, 45%).

EXAMPLE 9

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

When an equivalent amount of 1-methyl-5-(2-chloroethylthio)-1H-tetrazoleis substituted for 3,5-diethoxycarbonyl-1H-pyrazole and an equivalentamount of 2-bromochloroethane is substituted for 1,2-dibromoethane inthe procedure of Example 4,2-(1-methyl-5-(2-chloroethylthio)-1H-tetrazol-5-yl)ethyl chloride isisolated after column chromatography1-methyl-5-(2-chloroethylthio)-1H-tetrazole, Aldrich, 59%, A).

EXAMPLE 10

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

When an equivalent amount of 5-methylthio-1,3,4-thiadiazol-5-thione issubstituted for 3,5-diethoxycarbonyl-1H-pyrazole and an equivalentamount of 2-bromochloroethane is substituted for 1,2-dibromoethane inthe procedure of Example 4,2-(5-methylthio-1,3,4-thiadiazol-2-yl)thioethyl chloride is isolatedafter column chromatography (5-methylthio-1,3,4-thiadiazol-5-thione,Umfpathy et al., Synth. React. Inorg. Met.-Org. Chem., 1968, 16, p.1289, 41%, C).

EXAMPLE 11

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium ethoxide in ethanol.

When an equivalent amount of 5-phenyl-1,3,4-oxadiazole-5-thione issubstituted for 3,5-diethoxycarbonyl-1H-pyrazole and an equivalentamount of 2-bromochloroethane is substituted for 1,2-dibromoethane inthe procedure of Example 4,2-(2,3-dihydro-2-thioxo-5-phenyl-1,2,4-oxadiazol-3-yl)ethyl chloride isisolated after column chromatography(5-phenyl-1,3,4-oxadiazole-5-thione, El-Barbary et al., Chem. Acta.1985, 58, p. 71, 59%, ethyl acetate then methanol).

EXAMPLE 12

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

Sodium hydride (3.9 g, mmol, 50% mineral oil dispersion) was washed withhexane to remove mineral oil (3×10 ml) under a stream of nitrogen. Asolution of 1,3-benzoxazolin-2-one (Aldrich, 10 g, 74 mmol) indimethylformamide (DMF) (70 ml) was then added dropwise with stirring tothe hydride until hydrogen evolution ceased. The reaction flask wasimmersed in an ice bath and 2-bromochloroethane (12.3 ml, 148 mmol) indimethylformamide (30 ml) was added dropwise. The reaction mixture wasstirred at room temperature for 30 minutes, then heated to reflux for 3days. At the end of this time thin layer chromatography analysis showedconsumption of starting material. The reaction mixture was then cooledand the solvent evaporated under vacuum. The residue was worked-up asdescribed above and purified by column chromatography (400 g finesilica, chloroform-methanol-ammonium hydroxide, 80:1:0.1) to yield 11.7g (80%) of pure 2-(2-oxo-1,3-benzoxazolin-3-yl)ethyl chloride (mp.77°-79° C. as a pale orange solid.

EXAMPLE 13

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

When an equivalent amount of 1-ethyl-2-imidazolone is substituted for1,3-benzoxazolin-2-one and an equivalent amount of 1,2-dibromoethane issubstituted for 2-bromochloroethane in the procedure of Example 12,2-(3-ethyl-2,2-dihydro-2-oxo-1H-imidazol-1-yl)ethyl bromide is isolatedafter column chromatography (1-ethyl-2-imidazolone, Cortes et al., J.Org. Chem., 1983, 48, p. 2246, 17%, A).

EXAMPLE 14

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

When an equivalent amount of 1-ethyl-2,4-quinazolinedione is substitutedfor 1,3-benzoxazolin-2-one and an equivalent amount of 1,2-dibromoethaneis substituted for 2-bromochloroethane in the procedure of Example 12,2-(1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolin-3-yl)ethyl bromideis isolated after column chromatography (1-ethyl-2,4-quinazolinedione,Das et al., J. Indian Chem., 1963, 40, p. 35, 55%, crystallized frommethylene chloride).

EXAMPLE 15

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

When an equivalent amount of 2-pyrrolecarboxaldehyde is substituted for1,3-benzoxazolin-2-one in the procedure of Example 12,2-(2-formyl-1H-pyrrol-1-yl)ethyl chloride is isolated after columnchromatography (2-pyrrolecarboxaldehyde, Aldrich, 48%, I).

EXAMPLE 16

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

When an equivalent amount of 3-ethyluracil is substituted for1,3-benzoxazolin-2-one in the procedure of Example 12,2-(1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidin-1-yl)ethyl chloride isisolated after column chromatography (3-ethyluracil, Pogolotti et al.,J. Pharm. Sci., 1972, 61, p. 1423, 60%, C).

EXAMPLE 17

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

When an equivalent amount of oxindole is substituted for1,3-benzoxazolin-2-one in the procedure of Example 12,2-(2,3-dihydro-2-oxo-1H-indol-1-yl)ethyl chloride is isolated aftercolumn chromatography (oxindole, Aldrich, 15%, L).

Example 18

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in sodium hydride indimethylformamide.

When an equivalent amount of 1,4-benzothiazin-3(4H)-one is substitutedfor 1,3-benzoxazolin-2-one in the procedure of Example 12,2-(2,3-dihydro-3-oxo-4H-1,3-benzothiazin-4-yl)ethyl chloride is isolatedafter column chromatography (1,4-benzothiazin-3(4H)-one, Aldrich, 8%,G).

EXAMPLE 19

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

A solution of 1-ethoxycarbonyl-2H-indazolin-3-one (Wyrick et al., J.Med. Chem., 1984, 27, 768) (3 g, 14.5 mmol) intetrahydrofuran-dimethylformamide (THF-DMF) (25:5, ml) was added in oneportion to a stirred suspension of 1,2-dibromoethane (4.2 g, 29 mmol),crushed potassium hydroxide (KOH) (1.1 g, 16.7 mmol, 85.5%),tetrabutylammonium bromide (1.4 g, 4.4 mmol), and tetrahydrofuran (5ml). The reaction mixture was heated under reflux for 3 days at whichtime thin layer chromatography analysis showed the absence of startingmaterial and the emergence of two new spots. The product was worked-upas described above. The crude product was purified by gradient elutioncolumn chromatography (200 g fine silica; hexane-ethyl acetate, 7:1, toelute the first component; then 3:1 to 1:1 of the solvent system toelute the second component). The first component was identifiedspectroscopically as 3-(2-chloroethoxy)-1-ethoxycarbonyl-1H-indazole(2.2 g, 56%; Rf 0.34, hexaneethyl acetate, 3:1) and the second componentwas identified spectroscopically as1-ethoxycarbonyl-2-(2-chloroethyl)-2H-indazolin-3-one (0.6 g, 15%; Rf0.16). The first component was employed to prepare compounds of thepresent invention.

EXAMPLE 20

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of pyrithyldione is substituted for1-ethoxycarbonyl-2H-indazolin-3-one in the procedure of Example 19 usingtetrahydrofuran as solvent,2-(1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethyl-pyridin-1-yl)ethyl bromideis isolated after column chromatography (pyrithyldione, Aldrich, 52%,F).

EXAMPLE 21

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 5-isopropyl-1,2,4-triazolin-6-one issubstituted for 1-ethoxycarbonyl-2H-indazolin-3-one in the procedure ofExample 19 using toluene as solvent,2-(1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazin-1-yl)ethyl bromide isisolated after column chromatography (5-isopropyl-1,2,4-triazolin-6-one,Taylor et al., J. Heterocyclic Chem., 1985, 22, p. 409, 49%, J.)

EXAMPLE 22

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 1,8-naphthalene is substituted for1-ethoxycarbonyl-2H-indazolin-3-one in the procedure of Example 19 usingbenzene as solvent, 2-(N-(1,8-naphthalenecarboxyamidyl)ethyl bromide isisolated after column chromatography (1,8-naphthalene, Aldrich, 18%, C).

EXAMPLE 23

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 3-methylpyrazole is substituted for1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtoluene as solvent, 2-(3-methyl-1H-pyrazol-1-yl)ethyl chloride isisolated after column chromatography (3-methylpyrazole, Aldrich, 36%,C).

EXAMPLE 24

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 3,5-dimethylpyrazole is substituted for1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtetrahydrofuran as solvent, 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethylchloride is isolated after column chromatography (3,5-dimethylpyrazole,Aldrich, 24%, C).

EXAMPLE 25

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 4-iodopyrazole is substituted for1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtoluene as solvent, 2-(4-iodo-1H-pyrazol-1-yl)ethyl chloride is isolatedafter column chromatography (4-iodopyrazole, Aldrich, 41%, C).

EXAMPLE 26

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 1-phenyl-3(2H)-pyrazolinone is substitutedfor 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtetrahydrofuran as solvent,2-(2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazol1-yl)ethyl chloride isisolated after column chromatography (1-phenyl-3(2H)-pyrazolinone,Aldrich, 79%, J).

EXAMPLE 27

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 1-phenyl-3(2H)-pyrazolinone is substitutedfor 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtetrahydrofuran as solvent,2-(2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazol-1-yl)ethyl chloride isisolated after column chromatography (1-phenyl-3(2H)-pyrazolinone,Aldrich, 79%, J).

EXAMPLE 28

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 3-ethyl-3-phenylglutarimide is substitutedfor 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtetrahydrofuran as solvent, 2-(2,6-dioxo-3-ethyl-3-phenylpiperidin-1-yl)ethyl chloride is isolated after column chromatography(3-ethyl-3-phenylglutarimide, Tagmann, E. A. Helv. Chim. Acta, 1952, 35,p. 1541, 84%, C).

EXAMPLE .[.23.]. .Iadd.29 .Iaddend.

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 4-pyrimidone is substituted for1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19,2-(1,6-dihydro-6-oxopyrimidin-1-yl)ethyl chloride is isolated aftercolumn chromatography (4-pyrimidone, Aldrich, 34%, B).

EXAMPLE 30

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 2-methylthio-5-methyl-1,3-pyrimidin-6-oneis substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and2-bromochloroethane is substituted for 1,2-dibromoethane in theprocedure of Example 19 using tetrahydrofuran as solvent,2-(2-methylthio-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl)ethyl chlorideis isolated after column chromatography(2-methylthio-5-methyl-1,3-pyrimidin-6-one, Spengler et al., Arch.Pharm. (Weinheim). 1984, 317, p. 425, 26%, J).

EXAMPLE 31

This Example illustrates the preparation of halogenated heterocyclicalkyl electrophile intermediate compounds in the presence of phasetransfer catalysts.

When an equivalent amount of 3-ethyl-2-benzimidazolinone is substitutedfor 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane issubstituted for 1,2-dibromoethane in the procedure of Example 19 usingtetrahydrofuran as solvent,2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol1-yl)ethyl chloride isisolated after column chromatography (3-ethyl-2-benzimidazolinone,Aldrich, 6%, A).

EXAMPLE 32

This Example illustrates the preparation of tosylated heterocyclic alkylelectrophile intermediate compounds from alcohols.

Triethylamine (4.2 ml, 30 mmol was added, in one portion, and then, inportions, para-toluenesulfonyl chloride (5.7 g, 30 mmol was added, to asolution of 2-hydroxymethyl-1,4-benzodioxane (Maybridge, 5 g, 30 mmol)in methylene chloride (50 ml). A mild exothermic reaction ensued. Thereaction mixture was stirred overnight. Precipitated triethylaminehydrochloride was separated by filtration and washed with methylenechloride (50 ml). The organic medium was washed with 10% aqueoushydrochloric acid (50 ml, water 50 ml, brine (30 ml), and dried oversodium sulfate. Purification of the crude product by columnchromatography (400 g fine silica, hexane-ethyl acetatetriethylamine;100:100:1) yielded pure (1,4-benzodiozan-2-yl)methyl tosylate (66%).

EXAMPLE 33

This Example illustrates the preparation of tosylated heterocyclic alkylelectrophile intermediate compounds from alcohols.

When an equivalent amount of2-(2-hydroxyethyl)-2,3-dihydro-3(2H)-isoindolinone is substituted for2-hydroxymethyl-1,4-benzodioxane in the procedure of Example 32,2-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)ethyl tosylate is isolated aftercolumn chromatography(2-(2-hydroxyethyl)-2,3-dihydro-3(2H)-iso-indolinone, Minaskanian etal., Eur. Pat. Appl. EP 194685 A1 1986); Chem. Abstr., 1986, 106, 4894z,66%, mp. 75°-77.5° C., from ether).

EXAMPLE 34

This Example illustrates the preparation of chlorinated heterocyclicalkyl electrophile intermediate compounds from alcohols.

Thionyl chloride (SOCl₂, 6.2 ml) in chloroform (15 ml) was addeddropwise to an ice chilled solution of 2-(2-hydroxyethyl)pyridine(Aldrich, 10 g, 81 mmol in chloroform (10 ml. After addition wascomplete, the reaction mixture was stirred for 15 hours. The solvent andexcess thionyl chloride were removed on a vacuum rotary evaporatorfollowed by exposure to high vacuum (90 minutes, 0.5 mm Hg, 80° C.)Recrystallization of the crude brown solid from isopropanol-isopropylether yielded 10.8 g of pure 2-(2-pyridinyl)ethyl chloride hydrochloride(mp. 124°-125° C., lit. mp., about 120° C., Gump et al., U.S. Pat. No.2,533,243; Chem. Abstr., 1950, 45, p. 4271c) as light tan beads.

EXAMPLE 35

This Example illustrates the preparation of chlorinated heterocyclicalkyl electrophile intermediate compounds from alcohols.

When an equivalent amount of 4-methyl-5-(2-hydroxyethyl)thiazole issubstituted for 2-(2-hydroxyethyl) pyridine in the procedure of Example34 using benzene as solvent, 2-(4-methylthiazol-5-yl)ethyl chloridehydrochloride is isolated after column chromatography(4-methyl-5-(2-hydroxyethyl)thiazole, Aldrich, 71%, mp. 135°-137° C.,from isopropanol).

EXAMPLE 36

This Example illustrates the preparation of chlorinated heterocyclicalkyl electrophile intermediate compounds from alcohols.

When an equivalent amount of 3-(2-hydroxyethyl)pyridine is substitutedfor 2-(2-hydroxyethyl)pyridine in the procedure of Example 34,2-(3-pyridinyl)ethyl chloride hydrochloride is isolated after columnchromatography (3-(2-hydroxyethyl)pyridine, Tamura et al., Synthesis,1977, p. 1, 65% mp. 154°-155° C.).

EXAMPLE 37

This Example illustrates the preparation of compounds of the presentinvention.

In general, the compounds of the present invention were prepared byreacting a secondary amine intermediate compound of type 9 from Example1 (about 1 g) with a 10% excess of a heterocyclic alkyl electrophileintermediate compound of type 10 from Examples 2-36 in the presence ofan equivalent amount of sodium carbonate (about 1.5 g) and a catalyticamount of sodium iodide (about 100 mg) in refluxing acetonitrile. Whenthe electrophile intermediate compound was an alphahaloketone, thereaction was generally carried out at room temperature. Completion ofthe reaction was determined by the absence of starting materialaccording to thin layer chromatography analysis. The reaction mixturewas then filtered free of insoluble materials and the filtrate wasconcentrated under vacuum. The crude concentrate was partitioned between10% aqueous hydrochloric acid (40 ml) and ether (40 ml). The acidicaqueous layer was extracted with additional ether and then made alkalinewith 6N aqueous sodium hydroxide. The liberated free base was extractedwith methylene chloride (2×40 ml) and the organic extract was washedwith water (50 ml), brine (30 ml), and dried over sodium sulfate. Thecrude product was purified by column chromatography using fine silicaand eluting with choroform-methanol-ammonium hydroxides.

EXAMPLES 38-42

This Example illustrates the preparation of amino alcohol compounds ofthe present invention.

A quantity of sodium borohydride (NaBH₄, 100 mg) was added to a stirredsolution of the appropriate aminoketone (2 mmol) in absolute ethanol (10ml). Thin layer chromatography analysis of the reaction mixturegenerally showed complete reaction after 30 minutes of stirring at roomtemperature. The reaction mixture was then concentrated under vacuum andworked-up as described above. The crude product was purified by columnchromatography over the fine silica using the solvent systemchloroform-methanol-ammonium hydroxide.

The following amino alcohol compounds of the present invention wereprepared by the above procedure:

N-(phenyl)-N-[1-(2-hydroxy-2-(2-thienyl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(thienyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(1-methyl-2-hydroxy-2-(2-thienyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(2-furanyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(5-methyl-2-furanyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

EXAMPLE 43

This Example illustrates a general procedure for preparing compounds ofthe present invention.

A mixture of the appropriate secondary amine intermediate compound oftype 9 from Example 1 (Van Daele et al., J. Arzneim-Forsch. Drug Res.,1976, 26, p. 1521) (1.15 g, 4.2 mmol), 4-vinylpyridine (0.67 g, 6.3mmol), and 2-methoxyethanol (10 ml) was stirred under reflux overnight.At the end of this period, thin layer chromatography analysis of thereaction mixture showed complete reaction. The reaction was thenconcentrated under vacuum and the crude concentrate was partitionedbetween 10% aqueous hydrochloric acid (40 ml and ether (40 ml). Theacidic aqueous layer was extracted with additional ether and then madealkaline with 6N aqueous sodium hydroxide. The liberated free base wasextracted with methylene chloride (2×40 ml) and the organic extract waswashed with water (50 ml), brine (30 ml) and dried over sodium sulfate.The crude product was purified by column chromatography (135 g finesilica; chloroform-methanol-ammonium hydroxide; 40:1:0.01 to elute thefaster, excess 4-vinylpyridine; followed by flash chromatography; samecolumn; chloroform-methanol-ammonium hydroxide; 30:1:0.1 to yield pureN-phenyl)-N-[1-(2-(4-pyridinyl)ethyl)-4-methoxymethyl-4-piperidinyl]-propanamide(1.22 g, 74%) as a golden oil.

EXAMPLE 44

This Example illustrates a general procedure for preparing compounds ofthe present invention.

A mixture of the appropriate secondary amine intermediate compound oftype 9 from Example 1 (Van Daele et al., J. Arzneim-Forsch. Drug Res.,1976, 26, p. 1521) (0.94 g, 3.2 mmol, 3-(dimethylaminomethyl)-1H-indole(0.62 g, 3.6 mmol), NaI (about 100 mg), and 2-methoxyethanol (9 ml) wasstirred under reflux for 2 hours. A prominent odor of dimethylamine wasdetected. At the end of this period, thin layer chromatography analysisof the reaction mixture showed completion of the reaction. The reactionwas then concentrated under vacuum and the crude concentrate waspartitioned between 10% aqueous hydrochloride acid (40 ml) and ether (40ml). The acidic aqueous layer was extracted with additional ether andthen made alkaline with 6N aqueous sodium hydroxide. The liberated freebase was extracted with methylene chloride (2×40 ml) and the organicextract was washed with water (50 ml), brine (30 ml, and dried oversodium sulfate. The crude product was purified by flash columnchromatography (100 g fine silica; chloroform-methanol-ammoniumhydroxide, 30:1:0.01 to 20:1:0.1) to Yield pureN-(phenyl)-N-[1-(1H-indol-3-yl(methyl))-4-methoxy-carbonyl-4-piperidinyl]propanamide(0.95 g, 70%) as a cream colored solid.

EXAMPLE 45

This Example illustrates a general procedure for preparing compounds ofthe present invention having an R₂ clonidine substituent.

A mixture of 4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (7.34g, 25 mmol), 2-bromoethanol (3.96 g, 32 mmol), sodium carbonate (20.0 g,189 mmol), and sodium iodide (1.0 g) in acetonitrile (200 ml) was heatedto reflux for three days. The reaction mixture was cooled and filtered.The filtrate was concentrated under vacuum yielding an oily residue. Theresidue was chromatographed on silica gel (250 g; ethyl acetate/hexane;1:4) to yield1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine(8.1 g, 96%) as an oil.

A solution of methanesulfonyl chloride 0.374 g, 3.3 mmol in ethylacetate (3 ml was added to a mixture of1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine(1.0 g, 3 mmol) and triethylamine. The resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated under vacuum to give an oily residue. The residue waschromatographed on silica gel (290 g; ethyl acetate/hexane: 1:4) toyield1-(2-methanesulfonylethyl)-4-methoxycarbonyl-4-(N'-phenyl-propionamido)piperidine(0.53 g, 43%) as an oil.

A mixture of1-(2-methanesulfonylethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine(0.50 g, 1.2 mmol), clonidine hydrochloride (0.323 g, 1.2 mmol), andsodium carbonate (1.0 g, 9.4 mmol) in ethyl acetate (10 ml) was heatedto reflux for three days. The mixture was cooled and filtered and thefiltrate was evaporated under vacuum to give an oily residue. Theresidue was chromatographed on silica gel (25 g; ethyl acetate/methanol;4:1, 5% ammonium hydroxide in methanol) to yield1-[2-(2,6-di-chloroanilineO-2-imidazolin-1-yl]-ethyl-4-[N-phenylpropionamido]-4-methoxycarbonyl-piperidineas a crystalline solid (0.448 g, 68%), m.p. 75° C.

EXAMPLES 46-98

Further examples of compounds within the scope of the present inventionwhich may be prepared by procedures analogous to those described aboveinclude:

N-(phenyl)-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2-formyl)-1H-pyrrol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3-methyl-1H-pyrazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(4-iodo-1H-pyrazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3,5-diethoxycarbonyl-1H-pyrazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1H-imidazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(5-nitro-1H-imidazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(4,5-diethoxycarbonyl-1H-imidazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1H-imidazol-4-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl-N-[1-(2-(1-methyl-1H-imidazol-2-yl)-ethylthio)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1H-triazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(5-phenyl-2H-tetrazol-2-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1-methyl-1H-tetrazol-5-yl)-ethylthio)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-oxo-2-(2-thienyl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(2-thienyl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2-oxo-oxazol-3-yl)ethyl)-4methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2-phenyl-5oxo-1H-pyrazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazol-3-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(5-methylthio-1,3,4-thiadiazol-2-yl)ethylthio)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazol-3-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridin-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,6-dioxo-3-ethyl-3-phenylpiperidin-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1,6-dihydro-6-oxo-pyrimidin-1-yl)ethyl-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(2-methylthio-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidin-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,6-dihydro-6-oxo-3-methylpyridazin-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,6-dihydro-3-(2-propyl)-6-oxo-1,2,4-triazin-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(1H-indol-3-yl(methyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-1H-indol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)N-[1-(2-(2,3-dihydro-2-oxo-3,3-spiroethane-1H-indol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-ethyl-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-1-(2H-benzimidazol-1-yl(ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(0-(1-ethoxycarbonyl-1H-benzopyrazol-3-yl)-ethoxy)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-benzoxazol-3-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(5-chloro-2,3-dihydro-2-oxo-benzoxazol-3-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-oxo-2-(2,3-dihydro-2-oxo-benzoxazol-6-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(7-methoxy-2-oxo-2H-benzopyran-4-yl(methyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(1,4-benzodioxan-2-yl(methyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-3-oxo-4H-1,3-benzothiazin-4-yl)ethyl-4methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-oxo-3H-quinazolin-3-yl)ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolin-3-yl)ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1-ethyl-1,2,3,4-tetrahydro-2,4dioxo-3H-quinazolin-3-yl)ethyl))-4-methoxycarbonyl-4piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl))-4-methoxy-carbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)ethyl))-4-methoxy-carbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(N-1,8-naphthalene-sulfamidyl)ethyl))-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(N-1,8-naphthalene-dicarboxamidyl)ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3-thienyl)ethyl)-4-methoxycarbonyl-4piperidinyl]propanamide

EXAMPLES 99-135

Further examples of compounds within the scope of the present inventionwhich may be prepared by procedures analogous to those described aboveinclude:

N-(phenyl)-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2-formyl1H-pyrrol-1-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2(4-iodo-1H-pyrazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1H-imidazol-4-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1-methyl-1H-imidazol-2-yl)-ethylthio)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1H-triazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(5-trifluoromethyl-4-methyl-4H-triazol-3-yl)-ethylthio)-4methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(5-morpholinyl-2H-tetrazol-2-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(1methyl-2-oxo-2-(2-thienyl)-ethyl)methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(2-thienyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(1-methyl-2-hydroxy-2-(2-thienyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(2-furanyl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-hydroxy-2-(5-methyl-2-furanyl)ethyl)-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-imidazol-1-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]propanamideN-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2-phenyl-5oxo-1H-pyrazol-1-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,5-dihydro-3-methyl-4-amino-5-oxo-1H-triazol-1-yl-ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridin-1-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2-methylthio-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidin-1-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-1H-indol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-3,3-spiroethane-1H-indol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-1-(2-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-propanamide

N-(phenyl)-N-1-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-benzoxazol-3-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(2-oxo-2H-benzopyran-7-oxy)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(1,4-benzodioxan-2-yl(methyl))-4-methoxymethyl-piperidinyl]propanamide

N-(phenyl)-N-[1-(6-fluoro-1,3-benzodioxan-8-yl(methyl))-4-methoxymethyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(1-methyl-3,4-dihydro-4-oxo-3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-piperidinyl]propanamide

N-(phenyl)-N-[1-(2-(N-1,8-naphthalene-carboxamidyl)ethyl))-4-methoxymethyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(3-thienyl)ethyl)-4-methoxymethyl-4piperidinyl]propanamide

EXAMPLES 136-156

Further examples of compounds within the scope of the present inventionwhich may be prepared by procedures analogous to those described aboveinclude:

N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-2-methoxy-propanamide

N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide

N-(2-fluorophenyl)-N-[1-(2-(3-ethylbenzimid-azol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]methoxyacetamide

N-(2-fluorophenyl)-N-[1-(2-(2-methyl-5-nitroimidazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-methoxyacetamide

N-(phenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]acrylamide

N-(2-methoxyphenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-ethyl)-4-methoxymethyl)-4-piperidinyl]propanamide

N-(2-fluorophenyl)-N-[1-(2-(3-ethylbenzimid-azol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-propanamide

N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]methoxyacetamide

N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-ethyl)-4-methoxymethyl-4-piperidinyl]methoxyacetamide

N-(2-methoxyphenyl)-N-[1-(2-(N-phthalimidyl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(2-methoxyphenyl)-N-[1-(2-(3-ethylbenzimid-azol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(2-methoxyphenyl)-N-[1-(2-pyridinylethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

N-(2-methoxyphenyl)-N-[1(2-(1H-pyrazol-1-yl)-ethyl-4-methoxycarbonyl-4-piperidinyl]methoxyacetamide

N-(2-methoxyphenyl)-N-[1-(2-(1H-pyrazol-1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]methoxypropanamide

N-(2-methoxyphenyl)-N-[1-(2-(N-phthalimidyl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]methoxypropanamide

N-(phenyl)-N-[1-(2-(N-(2,6-dichloroaniline)-imidazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-propanamide

N-(phenyl)-N-[1-(2-(N-(2,6-dichloroaniline)-imidazol-1-yl)ethyl)-4-piperidinyl]propanamide

N-(2-fluorophenyl)-N-[1-(2-(1H-imidazol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide

EXAMPLES 157-172

Further examples of compounds within the scope of the present inventionwhich may be prepared by procedures analogous to those described aboveinclude:

trans-N-(2-fluorophenyl)-N-[1-((1H-benzimid-azol-2-yl)methyl)-3-methyl-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-((1H-benzimidazol-2-yl)methyl)-3-methyl-4-piperidinyl]methoxyacetamide

trans-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl-3-methyl-4-piperidinyl]methoxyacetamide

trans-N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-3-methyl-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)ethyl)-3-methyl-4-piperidinyl]-methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

cis-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-3-methyl-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-4-piperidinyl]methoxyacetamide

trans-N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)ethyl)-3-methyl-4-piperidinyl]propanamide

cis-N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

cis-N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)ethyl-3-methyl-4-piperidinyl]propanamide

cis-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-4-piperidinyl]propanamide

EXAMPLE 173

A pharmaceutical composition for parental or intravenous analgesicadministration can be prepared from the following ingredients:

    ______________________________________                                        COMPONENTS               AMOUNTS                                              ______________________________________                                        N-(phenyl)-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-                                                              1 mg                                                4-methoxycarbonyl-4-piperidinyl]propanamide                                   isotonic water           10 liters                                            ______________________________________                                    

Of course, other compounds of this invention such as those set out inExamples 46-172 may be substituted forN-(phenyl)-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamidewith the relative amount of such other compounds in the compositionsdepending upon their analgesic activity.

EXAMPLE 174

A number of compounds in accordance with the present invention weretested for their analgesic properties. Specifically, the acid additionsalts of the compounds, tested in accordance with the invention, weredissolved in sterile water for injection, USP, to form a solution, theconcentration of which may vary from 0.00001 mg/ml to 5 mg/ml. Thesolution was administered intravenously into a mouse tail vain. The ED50values were obtained from the mouse hot plate analgesia test 58° C. asdescribed in Domer, Floyd R., Animal Experiments in PharmacologicalAnalysis, Charles C. Thomas, Springfield, 1971, p. 283 ff. The compoundslisted in Tables 1 through 4 were tested by this Procedure and found tohave the activities listed in the columns on the right side of Tables 1through 4.

                                      TABLE 1                                     __________________________________________________________________________    COMPOUNDS                   M.P. °C.                                                                     ED.sub.50 Mg/Kg                             __________________________________________________________________________     1.                                                                             N-(phenyl)-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-                                                                191-192.5                                                                         0.00084                                       4-methoxycarbonyl-4-piperidinyl]propanamide                                  2.                                                                             N-(phenyl)-N-[1-(2-(2-formyl-1H-pyrrol-1-yl)-                                                           175-176                                                                             0.0026                                        ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      propanamide                                                                  3.                                                                             N-(phenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-                                                               184-187.5                                                                         0.0094                                        4-methoxycarbonyl-4-piperidinyl]propanamide                                  4.                                                                             N-(phenyl)-N-[1-(2-(3-methyl-1H-pyrazol-1-yl)-                                                          170-173                                                                             0.0038                                        ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      propanamide                                                                  5.                                                                             N-(phenyl)-N-[1-(2-(3,5-dimethyl-1H-pyrazol-                                                            204.5-205.5                                                                         0.0068                                        1-yl)-ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                propanamide                                                                  6.                                                                             N-(phenyl)-N-[1-(2-(4-iodo-1H-pyrazol-1-yl)ethyl)-                                                        163-164.5                                                                         0.017                                         4-methoxycarbonyl-4-piperidinyl]propanamide                                  7.                                                                             N-(phenyl)-N-[1-(2-(3,5-diethoxycarbonyl-1H-                                                            123-127                                                                             >1                                            pyrazol-1-yl)ethyl)-4-methoxycarbonyl-                                        4-piperidinyl]propanamide                                                    8.                                                                             N-(phenyl)-N-[1-(2-(1H-imidazol-1-yl)ethyl)-                                                            104-108                                                                             >1                                            4-methoxycarbonyl-4-piperidinyl]propanamide                                  9.                                                                             N-(phenyl)-N-[1-(2-(5-nitro-1H-imidazol-1-yl)-                                                          187-188                                                                             >5                                            ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      propanamide                                                                 10.                                                                             N-(phenyl)-N-[1-(2-(2-methyl-5-nitro-1H-                                                                186.5-188.5                                                                         0.264                                         imidazol-1-yl)-ethyl)-4-methoxycarbonyl-                                      4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(4,5-diethoxycarbonyl-                                                               152-153                                                                             >5                                            1H-imidazol-1-yl)-ethyl)-4-methoxycarbonyl-                                   4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1H-imidazol-4-yl)ethyl)-                                                            139.5-140                                                                           >5                                            4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(phenyl)-N-[1-(2-(1-methyl-1H-imidazol-2-yl)-                                                         168-172                                                                             0.129                                         ethylthio)-4-methoxycarbonyl-4-piperidinyl]-                                  propanamide                                                                   N-(phenyl)-N-[1-(2-(1H-triazol-1-yl)ethyl)-                                                             171-172                                                                             1.04                                          4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(phenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-                                                            198-200                                                                             0.185                                         4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(phenyl)-N-[1-(2-(5-phenyl-2H-tetrazol-2-yl)-                                                         130-140                                                                             >5                                            ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                                                (softens)                                           propanamide                                                                   N-(phenyl)-N-[1-(2-(1-methyl-1H-tetrazol-5-yl)-                                                         144-147                                                                             0.131                                         ethylthio)-4-methoxycarbonyl-4-piperidinyl]-                                  propanamide                                                                   N-(phenyl)-N-[1-(2-oxo-2-(2-thienyl)ethyl)-                                                             196-199                                                                             0.0436                                        4-methoxycarbonyl-4-piperidiny]propanamide                                    N-(phenyl)-N-[1-(2-hydroxy-2-(2-thienyl)ethyl)-                                                         179-180                                                                             0.0018                                        4-methoxycarbonyl-4-piperidinyl]propanamide                                 20.                                                                             N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2-oxo-                                                           160-163                                                                             >1                                            oxazol-3-yl)ethyl)-4-methoxycarbonyl-                                         4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2-phenyl-                                                        163.5-164.5                                                                         0.502                                         5-oxo-1H-pyrazol-1-yl)-ethyl)-4-methoxycarbonyl-                              4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2,4-dioxo-                                                       138-141                                                                             >1                                            5-methyl-5-phenyl-1H-imidazol-3-yl)ethyl)-4-                                  methoxycarbonyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(2-(5-methylthio-1,3,4-thiadiazol-                                                      144.5-147                                                                           0.19                                          2-yl)ethylthio)-4-methoxycarbonyl-4-piperidinyl]-                             propanamide                                                                   N-(phenyl)-N-[1-(2-(2,3-dihydro-2-thioxo-5-phenyl-                                                      140.5-142                                                                           >5                                            1,3,4-oxadiazol-3-yl)-ethyl)-4-methoxycarbonyl-4-                             piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-                                                       172-174                                                                             0.156                                         3,3-diethylpyridin-1-yl)-ethyl)-4-methoxycarbonyl-                            4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(2,6-dioxo-3-ethyl-3-                                                                121-124                                                                             0.462                                         phenylpiperidin-1-yl)ethyl)-4-methoxycarbonyl-                                4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,6-dihydro-6-oxo-pyrimidin-                                                        182-183                                                                             <1                                            1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                 propanamide                                                                   N-(phenyl)-N-[1-(2-(2-methylthio-1,6-dihydro-4-                                                           165-166.5                                                                         0.037                                         oxo-5-methylpyrimidin-1-yl)ethyl)-4-methoxycarbonyl-                          4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-                                                             193.5-196                                                                           2.67                                          dioxo-3-ethylpyrimidin-1-yl)-ethyl)-4-                                        methoxycarbonyl-4-piperidinyl]propanamide                                   30.                                                                             N-(phenyl)-N-[1-(2-(1,6-dihydro-6-oxo-3-                                                                158-160                                                                             0.051                                         methylpyridazin-1-yl)ethyl)-4-methoxycarbonyl-                                4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,6-dihydro-3-(2-propyl-                                                            148-152                                                                             0.621                                         6-oxo-1,2,4-triazin-1-yl)-ethyl-4-                                            methoxycarbonyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(1H-indol-3-yl(methyl))-                                                                188.5-190                                                                           >1                                            4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-1H-                                                               166-171                                                                             0.009                                         indol-1-yl)ethyl)-4-methoxycarbonyl-4-                                        piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(3,3-dimethyl-2,3-dihydro-                                                           184-185                                                                             0.038                                         2-oxo-1H-indol-1-yl)ethyl)-4-methoxycarbonyl-                                 4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-3,3-                                                              186.5-190                                                                           0.022                                         spiroethane-1H-indol-1-yl)ethyl)-4-methoxycarbonyl-                           4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,3-dihydro-1,3-dioxo-                                                              160-163                                                                             0.19                                          2H-isoindol-2-yl)-ethyl)-4-methoxycarbonyl-                                   4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2H-benzimidazol-1-yl)ethyl))-                                                          160-163                                                                             0.222                                         4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(phenyl)-N-[1-(0-(1-ethoxycarbonyl-1H-                                                                153-155                                                                             >5                                            benzopyrazol-3-yl)-ethoxy)-4-methoxycarbonyl-                                 4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-                                                                188-190                                                                             0.121                                         2-oxo-1H-benzimidazol-1-yl)ethyl)-4-                                          methoxycarbonyl-4-piperidinyl]propanamide                                   40.                                                                             N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-benzoxazol-                                                       134-138                                                                             0.0303                                        3-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                 propanamide                                                                   N-(phenyl)-N-[1-(2-(5-chloro-2,3-dihydro-                                                               180-181                                                                             0.272                                         2-oxo-benzoxazol-3-yl)-ethyl)-4-methoxycarbonyl-                              4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-oxo-2-(2,3-dihydro-2-oxo-                                                            215-217                                                                             >5                                            benzoxazol-6-yl)ethyl)-4-methoxycarbonyl-4-                                   piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(7-methoxy-2-oxo-2H-benzopyran-                                                         184-186                                                                             >5                                            4-yl(methyl))-4-methoxycarbonyl-4-piperidinyl]-                               propanamide                                                                   N-(phenyl)-N-[1-(1,4-benzodioxan-2-yl(methyl))-                                                         213.5-214                                                                           0.0503                                        4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(phenyl)-N-[1-(2-(2,3-dihydro-3-oxo-4H-1,3-                                                             215-218.5                                                                         0.047                                         benzothiazin-4-yl)ethyl))-4-methoxycarbonyl-4-                                piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-                                                             210-211                                                                             0.304                                         oxo-3H-quinazolin-3-yl)ethyl))-4-methoxycarbonyl-                             4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-                                                             190-193                                                                             >1                                            dioxo-3H-quinazolin-3-yl)ethyl))-4-methoxycarbonyl-                           4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1-ethyl-1,2,3,4-tetrahydro-                                                         224-228                                                                             0.19                                          2,4-dioxo-3H-quinazolin-3-yl)ethyl))-4-                                       methoxycarbonyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(2-(1,2,3,6-tetrahydro-1,3-                                                             194-195                                                                             >5                                            dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl))-                                     4-methoxycarbonyl-4-piperidinyl]propanamide                                 50.                                                                             N-(phenyl)-N-[1-(2-(1,2,3,6-tetrahydro-3,7-                                                             95    >5                                            dimethyl-2,6-dioxo-1H-purin-1-yl)ethyl))-4-                                   methoxycarbonyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(2-(N-1,8-naphthalenesulfamidyl)-                                                       212-214                                                                             0.223                                         ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamide                           N-(phenyl)-N-[1-(2-(N-1,8-naphthalene-                                                                  140-143                                                                             >1                                            dicarboxamidyl)ethyl))-4-methoxycarbonyl-                                     4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(3-thienyl)ethyl)-                                                                   192.5-193                                                                           0.0006                                        4-methoxycarbonyl-4-piperidinyl]propanamide                                 __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    COMPOUNDS                   M.P. °C.                                                                     ED.sub.50 Mg/Kg                             __________________________________________________________________________     1.                                                                             N-(phenyl)-N-[1-(2-(1H-pyrrol-1-yl)ethyl)-                                                              191-196                                                                             0.0029                                        4-methoxymethyl-4-piperidinyl]propanamide                                    2.                                                                             N-(phenyl)-N-[1-(2-(2-formyl-1H-pyrrol-1-yl)-                                                           172-175                                                                             0.0031                                        ethyl)-4-methoxymethyl-4-piperidiyl]propanamide                              3.                                                                             N-(phenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-                                                             169-170                                                                             0.0155                                        4-methoxymethyl-4-piperidinyl]propanamide                                    4.                                                                             N-(phenyl)-N-[1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-                                                        167-167.5                                                                         0.012                                         ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                             5.                                                                             N-(phenyl)-N-[1-(2-(4-iodo-1H-pyrazol-1-yl)ethyl)-                                                      184-186                                                                             0.018                                         4-methoxymethyl-4-piperidinyl]propanamide                                    6.                                                                             N-(phenyl)-N-[1-(2-(2-methyl-5-nitro-1H-imidazol-1-                                                     210-202                                                                             0.262                                         yl(ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                          7.                                                                             N-(phenyl)-N-[1-(2-(1H-imidazol-4-yl)ethyl-)                                                            152-153                                                                             >5                                            4-methoxymethyl-4-piperidinyl]propanamide                                    8.                                                                             N-(phenyl)-N-[1-(2-(1-methyl-1H-imidazol-2-yl)-                                                         163.5-164.5                                                                         0.13                                          ethylthio)-4-methoxymethyl-4-piperidinyl]propanamide                         9.                                                                             N-(phenyl)-N-[1-(2-(1H-triazol-1-yl)ethyl)-                                                             132.5-134.5                                                                         <1                                            4-methoxymethyl-4-piperidinyl]propanamide                                   10.                                                                             N-(phenyl)-N-[1-(2-(5-trifluoromethyl-4-methyl-4H-                                                      171.5-173.5                                                                         >1                                            triazol-3-yl)-ethylthio)-4-methoxymethyl-4-                                   piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(2H-tetrazol-2-yl)ethyl)-                                                            193   0.342                                         4-methoxymethyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(2-(5-morpholinyl-2H-tetrazol-2-yl)-                                                    153-154                                                                             >5                                            ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                              N-(phenyl)-N-[1-(1-methyl-2-oxo-2-(2-thienyl)ethyl)-                                                    74    >1                                            4-methoxymethyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(2-hydroxy-2-(2-thienyl)ethyl)-                                                           169-170.5                                                                         0.005                                         4-methoxymethyl-4-piperidinyl]8c propanamide                                  N-(phenyl)-N-[  1-(1-methyl-2-hydroxy-2-(2-thienyl)-                                                    171-174                                                                             0.015                                         ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                              N-(phenyl)-N-[1-(2-hydroxy-2-(2-furanyl)ethyl)-                                                         175-177                                                                             0.0034                                        4-methoxymethyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(2-hydroxy-2-(5-methyl-2-furanyl)-                                                      150-156                                                                             0.0092                                        ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                              N-(phenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-                                                       122-124                                                                             0.088                                         imidazol-1-yl)-ethyl)-4-methoxymethyl-4-piperidinyl]-                         propanamide                                                                   N-(phenyl)-N-[1-(2-(2,3,4,5-tetrahydro-2-phenyl-5-                                                      86-89 >1                                            oxo-1H-pyrazol-1-yl)-ethyl)-4-methoxymethyl-4-                                piperidinyl]propanamide                                                     20.                                                                             N-(phenyl)-N-[1-(2-(1,5-dihydro-3-methyl-4-amino-5-                                                     95    >5                                            oxo-1H-triazol-1-yl)-ethyl)-4-methoxymethyl-4-                                piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3,3-                                                     159-161.5                                                                         0.176                                         diethylpyridin-1-yl)-ethyl)-4-methoxymethyl-4-                                piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(2-methylthio-1,6-dihydro-4-                                                         168.5-169.5                                                                         0.055                                         oxo-5-methylpyrimidin-1-yl)ethyl)-4-methoxymethyl-                            4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,2,3,4-tetrahydro-2,4-dioxo-3-                                                     158-160                                                                             0.602                                         ethylpyrimidin-1-yl)-ethyl)-4-methoxymethyl-4-                                piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-1H-indol-1-yl)-                                                   108.5-112                                                                           0.0027                                        ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                              N-(phenyl)-N-[1-(2-(3,3-dimethyl-2,3-dihydro-2-oxo-                                                     186.5-190                                                                           0.027                                         1H-indol-1-yl)ethyl)-4-methoxymethyl-4-                                       piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-3,3-                                                              194.5-196.5                                                                         0.064                                         spiroethane-1H-indol-1-yl)ethyl)-4-methoxymethyl-                             4-piperidinyl]propanamide                                                     N-(phenyl)-N-[1-(2-(1,3-dihydro-1-oxo-2H-                                                               160-163                                                                             1.5                                           isoindol-2-yl)ethyl)-4-methoxymethyl-4-                                       piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(1,3-dihydro-1,3-dioxo-                                                              172.5-174.5                                                                         0.799                                         2H-isoindol-2-yl)-ethyl)-4-methoxymethyl-4-                                   piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-                                                       191.5-192.5                                                                         0.092                                         benzimidazol-1-yl)ethyl)-4-methoxymethyl-4-                                   piperidinyl]propanamide                                                     30.                                                                             N-(phenyl)-N-[1-(2-(2,3-dihydro-2-oxo-benzoxazol-                                                       194-195                                                                             0.10                                          3-yl)ethyl)-4-methoxymethyl-4-piperidinyl]propanamide                         N-(phenyl)-N-[1-(2-(2-oxo-2H-benzopyran-7-oxy)ethyl)-                                                   110-113                                                                             >5                                            4-methoxymethyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(1,4-benzodioxan-2-yl(methyl))-                                                         200-202                                                                             0.10                                          4-methoxymethyl-4-piperidinyl]propanamide                                     N-(phenyl)-N-[1-(6-fluoro-1,3-benzodioxan-8-                                                            186-197                                                                             >1                                            yl(methyl))-4-methoxymethyl-4-piperidinyl]-                                   propanamide                                                                   N-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-oxo-                                                         214.5-216.5                                                                         0.424                                         3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-                                 piperidinyl]propanamide                                                       N-(phenyl)-N-[1-(2-(1-ethyl-1,2,3,4-tetrahydro-                                                         189-190                                                                             0.148                                         2,4-dioxo-3H-quinazolin-3-yl)ethyl))-4-                                       methoxymethyl-4-piperidinyl]propanamide                                       N-(phenyl)-N-[1-(2-(N-1,8-naphthalenecarboxamidyl)-                                                     95    0.496                                         ethyl))-4-methoxymethyl-4-piperidinyl]propanamide                             N-(phenyl)-N-[1-(2-(3-thienyl)ethyl)-                                                                   177-179                                                                             0.0038                                        4-methoxymethyl-4-piperidinyl]propanamide                                   __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    COMPOUNDS                  M.P. °C.                                                                    ED.sub.50 Mg/Kg                               __________________________________________________________________________     1.                                                                             N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)-                                                          186-188                                                                             0.0021                                         ethyl)-4-methoxycarbonyl-4-piperidinyl)]-                                     propanamide                                                                  2.                                                                             N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-                                                           150-154                                                                            0.196                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      propanamide                                                                  3.                                                                             N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-                                                           135-140                                                                            1.5                                             ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      2-methoxypropanamide                                                         4.                                                                             N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)-                                                          172-173                                                                            0.016                                           ethyl)-4-methoxymethyl-4-piperidinyl]-                                        propanamide                                                                  5.                                                                             N-(2-fluorophenyl)-N-[1-(2-(3-ethylbenzimidazol-                                                       168-169                                                                            0.367                                           1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-                                   methoxyacetamide                                                             6.                                                                             N-(2-fluorophenyl)-N-[1-(2-(2-methyl-5-                                                                145-148                                                                            0.937                                           nitroimidazol-1-yl)ethyl)-4-methoxymethyl-                                    4-piperidinyl]methoxyacetamide                                               7.                                                                             N-(phenyl)-N-[1-(2-(1H-pyrazol-1-yl)ethyl)-                                                            208  0.012                                           4-methoxycarbonyl-4-piperidinyl]acrylamide                                   8.                                                                             N-(2-methoxyphenyl)-N-[1-(2-(1H-pyrazol-1-yl)-                                                         193-195                                                                            0.026                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      propanamide                                                                  9.                                                                             N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-                                                           165-167                                                                            0.683                                           ethyl)-4-methoxymethyl-4-piperidinyl]-                                        propanamide                                                                 10.                                                                             N-(2-fluorophenyl)-N-[1-(2-(3-ethylbenzimidazol-                                                       182-183                                                                            0.12                                            1-yl)ethyl)-4-methoxymethyl-4-piperidinyl]-                                   propanamide                                                                   N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)-                                                          161-163                                                                            0.12                                            ethyl)-4-methoxymethyl-4-piperidinyl]-                                        methoxyacetamide                                                              N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-                                                           130-135                                                                            0.468                                           ethyl)-4-methoxymethyl-4-piperidinyl]-                                        methoxyacetamide                                                              N-(2-methoxyphenyl)-N-[1-(2-(N-phthalimidyl)-                                                          163-166                                                                            0.106                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      propanamide                                                                   N-(2-methoxyphenyl)-N-[1-(2-(3-ethylbenzimidazol-                                                      166-168                                                                            0.094                                           1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                 propanamide                                                                   N-(2-methoxyphenyl-N-[1-(2-pyridinylethyl-                                                             155-158                                                                            0.020                                           4-methoxycarbonyl-4-piperidinyl]propanamide                                   N-(2-methoxyphenyl)-N-[1-(2-(1H-pyrazol-1-yl)-                                                         172-173                                                                            0.309                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      methoxyacetamide                                                              N-(2-methoxyphenyl)-N-[1-(2-(1H-pyrazol 1-yl)-                                                         190-192                                                                            0.149                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      methoxypropanamide                                                            N-(2-methoxyphenyl)-N-[1-(2-(N-phthalimidyl)-                                                          174-175                                                                            0.389                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                      methoxypropanamide                                                            N-(phenyl)-N-[1-(2-(N-(2,6-dichloroaniline)-                                                           103  2                                               imidazol-1-yl)ethyl)-4-methoxycarbonyl-4-                                     piperidinyl]propanamide                                                     20.                                                                             N-(2-fluorophenyl)-N-[1-(2-(2-methyl-1H-imidazol-                                                       92  5                                               1-yl)ethyl)-4-methoxycarbonyl-4-piperidinyl]-                                 propanamide                                                                   N-(2-fluorophenyl)-N-[1-(2-(1H-imidazol-1-yl)-                                                         120  0.171                                           ethyl)-4-methoxycarbonyl-4-piperidinyl]propanamide                          __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    COMPOUNDS                  M.P. °C.                                                                    ED.sub.50 Mg/Kg                               __________________________________________________________________________     1.                                                                             trans-N-(2-fluorophenyl)-N-[1-((1H-benzimidazol-                                                       134-136                                                                            >5                                              2-yl)methyl)-3-methyl-4-piperidinyl]-                                         methoxyacetamide                                                             2.                                                                             cis-N-(2-fluorophenyl)-N-[1-((1H-benzimidazol-                                                         144-145                                                                            >5                                              2-yl)methyl)-3-methyl-4-piperidinyl]-                                         methoxyacetamide                                                             3.                                                                             trans-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-                                                         160-161                                                                            2.5                                             2-yl)ethyl)-3-methyl-4-piperidinyl]propanamide                               4.                                                                             trans-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-                                                         177-178                                                                            6.0                                             2-yl)ethyl)-3-methyl-4-piperidinyl]methoxyacetamide                          5.                                                                             trans-N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-                                                          135-136                                                                            2.5                                             1-yl)ethyl)-3-methyl-4-piperidinyl]methoxyacetamide                          6.                                                                             cis-N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-                                                       124-126                                                                            0.5                                             ethyl)-3-methyl-4-piperidinyl]methoxyacetamide                               7.                                                                             cis-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-                                                         96-97                                                                              0.174                                           yl)ethyl)-3-methyl-4-piperidinyl]propanamide                                 8.                                                                             cis-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-                                                         117-118                                                                            0.329                                           yl)ethyl)-3-methyl-4-piperidinyl]methoxyacetamide                            9.                                                                             cis-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-                                                           182-183                                                                            0.0058                                          dihydro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-                                  methyl-4-piperidinyl]methoxyacetamide                                       10.                                                                             trans-N-(2-fluorophenyl)-N-[1-(2-N-phthalimidyl)-                                                      163-164                                                                            1.8                                             ethyl)-3-methyl-4-piperidinyl]propanamide                                     cis-N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-1-yl)-                                                      114-115                                                                            0.0015                                          ethyl)-3-methyl-4-piperidinyl]propanamide                                     trans-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-                                                         186-187                                                                            0.085                                           dihyro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-                            4-piperidinyl]propanamide                                                     trans-N-(2-fluorophenyl)-N-[1-(2-(1H-pyrazol-                                                          157-158                                                                            0.044                                           1-yl)ethyl)-3-methyl-4-piperidinyl]propanamide                                cis-N-(2-fluorophenyl)-N-[1-(2-(N-phthalimidyl)-                                                       153-154                                                                            0.275                                           ethyl)-3-methyl-4-piperidinyl]  propanamide                                   cis-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-dihyro-                                                    175-176                                                                            0.0174                                          2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-4-                                 piperidinyl]propanamide                                                       trans-N-(2-fluorophenyl)-N-[1-(2-(3-ethyl-2,3-                                                         154-155                                                                            >5                                              dihyro-2-oxo-1H-benzimidazol-2-yl)ethyl)-3-methyl-                            4-piperidinyl]propanamide                                                   __________________________________________________________________________

It will be understood that the embodiments described herein are merelyexemplary and that a person skilled in the art may make many variationsand modifications without departing from the spirit and scope of theinvention. All such modifications and variations are intended to beincluded within the scope of the invention as defined in the appendedclaims.

We claim:
 1. A compound having the formula: ##STR22## optically activeisometric forms thereof, and pharmaceutically acceptable acid additionsalts thereof, wherein:R is selected from the group consisting of phenyland substituted phenyl, wherein said substituents are membersindependently selected from the group consisting .[.one or more ofhalogen.]. .Iadd.of one or more of halo and lower alkoxy.Iaddend.; R₁ isselected form the group consisting of lower alkyl, lower-alkenyl, and alower-alkoxy lower-alkyl group having from 2 to 6 carbon atoms; R₂ is a.[.quniazolyl.]. .Iadd.quinazolinyl .Iaddend.lower-alkyl group or apurinyl lower-alkyl group, the lower-alkyl portion of said groupscontaining from 1 to 7 carbon atoms and the heterocyclic portion thereofbeing unsubstituted or substituted with one or more substituentsselected from the group consisting of .[.halogen.]. .Iadd.halo,oxo.Iaddend., hydroxyl, nitro, amino, lower-alkoxy carbonyl,lower-alkyl, lower-cycloalkyl, lower alkoxy, halogenated lower-alkyl,aryl and halogenated aryl; and R₃ is lower-alkoxy carbonyl orlower-alkoxy methyl.
 2. A compound according to claim 1, wherein R isselected from the group consisting of phenyl, 2-fluorophenyl and2-methoxyphenyl.
 3. A compound according to claim 1, wherein R₁ isselected from the group consisting of ethyl, ethenyl, methoxymethyl and1-methoxyethyl.
 4. A compound according to claim 1, wherein R₂ isselected from the group consisting of substituted or unsubstitutedquinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yllower-alkyl groups.
 5. A compound according to claim 1, wherein R₃ ismethoxy carbonyl or methoxymethyl.
 6. A compound according to claim 1,wherein R is a phenyl group;R₂ is a substituted or unsubstituted.Iadd.quinazolinyl .Iaddend.lower-alkyl group or purinyl lower-alkylgroup; and R₃ is a lower-alkoxy carbonyl group.
 7. A compound accordingto claim 6, wherein R₁ is ethyl.
 8. A compound according to claim 6,wherein R₂ is selected from the group consisting of substituted orunsubstituted quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl andpurin-7-yl lower alkyl groups.
 9. A compound according to claim 1,wherein R is a phenyl group;R₂ is a substituted or unsubstitutedquinazolinyl lower-alkyl group or purinyl lower-alkyl group; and R₃ is alower-alkoxy methyl group.
 10. A compound according to claim 9, whereinR₁ is ethyl and R₃ is methoxymethyl.
 11. A compound in accordance withclaim 6, which .[.comprises.]. .Iadd.consists of.Iaddend.N-(phenyl-N-[1-(2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-pyrin-7-yl)ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamideor a pharmaceutically acceptable acid addition salt thereof.
 12. Acompound in accordance with claim .[.6.]. .Iadd.10.Iaddend., which.[.comprises.]. .Iadd.consists of.Iaddend.N-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-oxo-3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-piperidinyl]propanamideor a pharmaceutically acceptable acid addition salt thereof.
 13. Acompound according to claim 9, wherein R₂ is selected from the groupconsisting of substituted or unsubstituted quinazolin-3-yl lower alkyl,purin-1-yl lower-alkyl and purin-7-yl lower-alkyl groups.
 14. Ananalgesic composition comprising a non-toxic pharmaceutically acceptablecarrier and an analgesically effective amount of a compound as definedin claim
 1. 15. The composition according to claim 14, wherein R isselected from the group consisting of phenyl, 2-fluorophenyl and2-methoxyphenyl.
 16. The composition according to claim 14, wherein R₁is selected from the group consisting of ethyl, ethenyl, methoxymethyland 1-methoxyethyl.
 17. A composition according to claim 14, wherein R₂is selected from the group consisting of substituted or unsubstitutedquinazolinyl-3-yl lower-alkyl, purin-1-yl, lower-alkyl and purin-7-yllower-alkyl groups.
 18. A composition according to claim 14, wherein R₃is methoxy carbonyl or methoxymethyl.
 19. A composition according toclaim 14, wherein R is a phenyl group;R₂ is .[.substituted or.]..Iadd.selected from the group consisting of substituted and.Iaddend.unsubstituted quinazolinyl lower-alkyl group or purinyllower-alkyl group; and R₃ is lower-alkoxy carbonyl group.
 20. Acomposition according to claim 19, wherein R₁ is ethyl.
 21. Acomposition according to claim 19, wherein R₃ is methoxy carbonyl.
 22. Acomposition according to claim 19, wherein R₂ is selected from the groupconsisting of substituted or unsubstituted quinazolin-3-yl lower-alkyl,purin-1-yl lower-alkyl and purin-7-yl lower-alkyl groups.
 23. Acomposition in accordance with claim 14, wherein the compound comprisesN-(phenyl)-N-[1-(2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl))-4-methoxy-carbonyl-4-piperidinyl]propanamideor a pharmaceutically acceptable acid addition salt thereof.
 24. Acomposition in accordance with claim 14, wherein the compound comprisesN-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-oxo-3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-piperidinyl]propanamideor a pharmaceutically acceptable acid addition salt thereof.
 25. Amethod for producing analgesia in a mammal in need thereof comprisingadministering to the mammal an analgesically effective amount of acompound as defined in claim
 1. 26. A method according to claim 25,wherein R is selected from the group consisting of phenyl,2-fluorophenyl and 2-methoxyphenyl.
 27. A method according to claim 25,wherein R₁ is selected from the group consisting of ethyl, ethenyl,methoxymethyl and 1-methoxyethyl.
 28. A method according to claim 25,wherein R is a phenyl group;R₂ is selected from the group consisting ofsubstituted .[.or.]. .Iadd.and .Iaddend.unsubstituted quinazolinyllower-alkyl and purinyl lower-alkyl groups; and R₃ is a lower-alkoxycarbonyl group.
 29. A method according to claim 25, wherein R₂ isselected from the group consisting of substituted or unsubstitutedquinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yllower-alkyl.
 30. A method according to claim 28, wherein R₂ is selectedfrom the group consisting of substituted or unsubstitutedquinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yllower-alkyl groups.